Methods and compositions for regulating bone and cartilage formation

ABSTRACT

The invention provides methods and compositions for diagnostic assays for detecting bone and cartilage formation and therapeutic methods and compositions for treating disease and disorders related to bone and cartilage formation or resorption, such as osteoporosis and bone fractions. The invention also provides therapeutic methods for diseases related to bone or cartilage formation or resorption. Methods for identifying therapeutics for such diseases are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.10/125,691, entitled “Methods and Compositions for Regulating Bone andCartilage Formation”, filed Apr. 18, 2002, which application claims thebenefit of U.S. Provisional Application No. 60/284,786, filed on Apr.18, 2001. The contents of both applications are specificallyincorporated by reference herein.

BACKGROUND OF THE INVENTION

Bone formation is an essential process in embryonic development andplays a critical role in many diseases and conditions which affectmillions of humans. For example, osteoporosis is a debilitating diseasecharacterized by excessive bone loss that affects approximately 14million Americans and costs the U.S. health care system nearly $10billion annually. In about 40 percent of women and 13 percent of menover 50, osteoporosis is the underlying cause of most hip, spine, andwrist fractures. Recent studies estimate that as much as 70 percent ofthe variation in bone density is inherited. Bone density reaches adultlevels at approximately 18-22 years of life and remains relativelystable until middle age. Loss of bone density in the elderly is theconsequence of known factors such as menopause, inadequate nutrition,specific medical conditions, and unknown factors such as a person'sgenetic constitution. Physicians have very few available drugs to treatdeclining bone density and need drugs that will promote bone formationin patients.

Bone is continuously remodeled through a coupled process of boneresorption and bone formation. During bone resorption, osteoclastsattach to the mineralized bone matrix and excavate small pits on thebone surface, releasing bone collagen and minerals in the circulation.Subsequently, cross-linked N-telopeptides are released into thebloodstream during osteoclastic activity. During bone formation,osteoblasts are recruited to the newly resorbed areas on the bone wherethey deposit new collagen. When resorption and formation are in balance,there is no net change in bone mass. After a resting phase during whichthe bone is mineralized, the remodeling cycle begins again.

In addition to bone formation, another important role forosteoprogenitor cells is in vascular calcification (see, e.g. Curr OpinNephrol Hypertens (2000) 9: 11-15). Calcification is a component ofvascular disease that usually occurs in concert with atheroma formationbut through distinct pathophysiological processes. Vessel wallosteoprogenitor cells known as calcifying vascular cells can form bonematrix proteins and calcified nodules, analogous to osteoblasticdifferentiation in bone. These cells have been isolated from the tunicamedia of bovine and human arteries, and both in-vitro tissue culturemodels and mouse models of vascular calcification have been established.Studies of the effects of diabetes mellitus, hyperlipidemia, estrogensand glucocorticoids on calcifying vascular cell function provide insightinto the relationship between common human disease states and vascularcalcification.

While endochondral bone formation has been fairly well characterizedfrom a morphological perspective, this process remains largely undefinedat a gene transcriptional level. In vitro and in vivo studies havesuggested that bone morphogenetic protein-2 (BMP-2) plays an importantrole in bone formation, however a detailed understanding of themolecular mechanisms involved would be useful to identify potentialgenetic targets for controlling bone formation. Accordingly, anunderstanding of the biochemical and molecular events underlying boneformation, and in particular the identity of the gene(s) expressedduring bone and cartilage formation, would provide significantdiagnostic and therapeutic applications for the treatment of diseasesrelating to bone and cartilage formation or resorption, such asosteoporosis, bone fractures and rheumatoid arthritis.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides computer-readable mediacomprising a plurality of digitally encoded values representing thelevels of expression of a plurality of genes listed in Table 1, 2, 5, 6and/or 7 during bone or cartilage formation. The computer-readablemedium may comprise values representing levels of expression of at least5 genes listed in Table 1, 2, 5, 6 and/or 7. The computer-readablemedium may comprise values representing levels of expression of CLF-1and MMP23 during bone or cartilage formation. The computer-readablemedium may comprise values representing levels of expression of aplurality of genes listed in Table 6. The computer-readable medium mayfurther comprise at least one value representing a level of expressionof at least one gene that is up- or down-regulated during bone orcartilage formation in a precursor cell. In other embodiments, thecomputer-readable medium may comprise at least one value representing alevel of expression of at least one gene that is up- or down-regulatedduring a particular stage of bone or cartilage formation. Further, thecomputer-readable medium may comprise values representing levels ofexpression of at least one of Cyr61, Col2a1, Runx2, and Ctsk during boneor cartilage formation. In certain embodiments, the computer-readablemedium may comprise values representing levels of expression of aplurality of genes listed in Table 7. In still other embodiments, thecomputer-readable medium may comprise at least one value representing alevel of expression of at least one gene that is co-regulated orfunctionally connected with a gene that is up- or down-regulated duringa particular stage of bone or cartilage formation. The values on thecomputer-readable medium may represent ratios of, or differencesbetween, a level of expression of a gene in one sample and the level ofexpression of the gene in another sample. In certain embodiments, lessthan about 50% of the values in the computer-readable medium representexpression levels of genes which are not listed in Table 1, 2, 5, 6and/or 7.

In another embodiment, the invention provides computer systems,comprising, e.g., a database comprising values representing expressionlevels of a plurality of genes listed in Table 1, 2, 5, 6 and/or 7during bone or cartilage formation; and, a processor having instructionsto, receive at least one query value representing at least one level ofexpression of at least one gene listed in Table 1, 2, 5, 6 and/or 7;and, compare the at least one query value and the at least one databasevalue. The query value may represent the level of expression of a genelisted in Table 1, 2, 5, 6 and/or 7 in a diseased cell of a subjecthaving or susceptible of having a disease selected from the groupconsisting of osteodystrophy, osteohypertrophy, osteoblastoma,osteopertrusis, osteogenesis imperfecta, osteoporosis, osteopenia,osteoma and osteoblastoma; periodontal disease; hyperparathyroidism;hypercalcemia of malignancy; Paget's disease; osteolytic lesionsproduced by bone metastasis; bone loss due to immobilization or sexhormone deficiency; bone and cartilage loss caused by an inflammatorydisease, rheumatoid arthritis, osteoarthritis and bone fractures.Further, the query value may represent the level of expression of a genelisted in Table 1, 2, 5, 6 and/or 7 in a precursor cell for which thestage of bone or cartilage formation is unknown.

The invention further provides computer programs for analyzing levels ofexpression of a plurality of genes listed in Table 1, 2, 5, 6 and/or 7in a cell, the computer program being disposed on a computer readablemedium and including instructions for causing a processor to: receivequery values representing levels of expression of a plurality of geneslisted in Table 1, 2, 5, 6 and/or 7 in a query cell, and, compare thequery values with levels of expression of the plurality of genes listedin Table 1, 2, 5, 6 and/or 7 in a reference cell.

Also provided by the invention are compositions comprising a pluralityof detection agents of genes listed in Table 1, 2, 5, 6 and/or 7, whichdetection agents are capable of detecting the expression of the genes orthe polypeptides encoded by the genes, and wherein, e.g., less thanabout 50% of the detection agents are of genes which are not listed inTable 1, 2, 5, 6 and/or 7. The composition may comprise detection agentsof CLF-1 or MMP23. Other compositions comprise detection agents ofCyr61, Col2a1, Runx2, or Ctsk. Still other compositions comprisedetection agents of genes having expression profiles similar to Cyr61,Col2a1, Runx2, or Ctsk. The detection agents may be isolated nucleicacids that hybridize specifically to nucleic acids corresponding to thegenes, e.g., at least about 5, 10 or 100 genes of Table 6. Othercompositions comprise a plurality of antagonists of a plurality of geneslisted in Table 1, 2, 5, 6 and/or 7, e.g., antisense nucleic acids,siRNAs, ribozymes or dominant negative mutants. Yet other compositionscomprise a plurality of agonists of a plurality of genes listed in Table1, 2, 5, 6 and/or 7.

Also within the scope of the invention are solid surfaces to which arelinked a plurality of detection agents of genes which are listed inTable 1, 2, 5, 6 and/or 7, which detection agents are capable ofdetecting the expression of the genes or the polypeptides encoded by thegenes, and wherein, e.g., less than about 50% of the detection agentsare not detecting genes listed in Table 1, 2, 5, 6 and/or 7. Thedetection agents may be isolated nucleic acids that hybridizespecifically to the genes. The detection agents may be covalently linkedto the solid surface.

Also provided are methods for determining the difference between levelsof expression of a plurality of genes in Table 1, 2, 5, 6 and/or 7 in acell and reference levels of expression of the genes, comprising, e.g.,providing RNA from the cell; determining levels of RNA of a plurality ofgenes listed in Table 1, 2, 5, 6 and/or 7 to obtain the levels ofexpression of the plurality of genes in the cell; and comparing thelevels of expression of the plurality of genes in the cell to a set ofreference levels of expression of the genes, to thereby determine thedifference between levels of expression of the plurality of genes listedin Table 1, 2, 5, 6 and/or 7 in the cell and reference levels ofexpression of the genes. The set of reference levels of expression mayinclude the levels of expression of the genes during bone or cartilageformation. The set of reference levels of expression may also includethe levels of expression of the genes during a particular stage of boneor cartilage formation. The set of reference levels of expression mayfurther include the levels of expression of the genes in a precursorcell. The set of reference levels of expression may further include thelevels of expression of the genes during a stage of bone or cartilageformation in a precursor cell. The cell may be a cell of a subjecthaving or susceptible of having a disease selected from the groupconsisting of osteodystrophy, osteohypertrophy, osteoblastoma,osteopertrusis, osteogenesis imperfecta, osteoporosis, osteopenia,osteoma and osteoblastoma; periodontal disease; hyperparathyroidism;hypercalcemia of malignancy; Paget's disease; osteolytic lesionsproduced by bone metastasis; bone loss due to immobilization or sexhormone deficiency; bone and cartilage loss caused by an inflammatorydisease, rheumatoid arthritis, osteoarthritis and bone fractures. Themethod may comprise incubating a nucleic acid sample derived from theRNA of the cell of the subject with nucleic acids corresponding to thegenes, under conditions wherein two complementary nucleic acidshybridize to each other. The nucleic acids corresponding to the genesmay be attached to a solid surface. The method may comprise entering thelevels of expression of the plurality of genes into a computer thatcomprises a memory with values representing the set of reference levelsof expression. Comparing the level may comprise providing to thecomputer instructions to perform.

In another embodiment, the invention provides methods for determiningwhether a subject has or is likely to develop a disease related to boneor cartilage resorption, comprising, e.g., obtaining a biological samplefrom the subject and comparing gene expression levels in the biologicalsample to those of a set of reference levels of expression during normalbone and cartilage formation, wherein significant differences in thelevels of expression of the plurality of genes indicates that thesubject has or is likely to develop a disease related to bone orcartilage resorption. The disease may be selected from the groupconsisting of osteoporosis, osteopenia, periodontal disease; osteolyticlesions produced by bone metastasis; bone loss due to immobilization orsex hormone deficiency; bone and cartilage loss caused by aninflammatory disease, rheumatoid arthritis and osteoarthritis.

In another embodiment, the invention provides methods for determiningwhether a subject has or is likely to develop a disease related to boneor cartilage formation, comprising, e.g., obtaining a biological samplefrom the subject and comparing gene expression levels in the biologicalsample to those of a set of reference levels of expression during normalbone and cartilage formation, wherein significant similarities in thelevels of expression of the plurality of genes indicates that thesubject has or is likely to develop a disease related to bone orcartilage formation. The disease may be selected from the groupconsisting of osteodystrophy, osteohypertrophy, osteoblastoma,osteopertrusis, osteogenesis imperfecta, osteoma and osteoblastoma,hyperparathyroidism; hypercalcemia of malignancy; and Paget's disease.

In yet another embodiment, the invention provides methods fordetermining the effectiveness of a treatment intended to stimulate boneor cartilage formation, comprising, e.g., obtaining a biological samplefrom the subject and comparing gene expression levels in the biologicalsample to those of a set of reference levels of expression during normalbone and cartilage formation, wherein significant similarities in thelevels of expression of the plurality of genes indicates that thetreatment is effective. The biological sample may be obtained from thehealing region of a bone fracture and a similarity in levels ofexpression of the plurality of genes in the cell of the subject and thereference levels of expression indicates that the fracture is healing.The method may further comprise iteratively providing a biologicalsample from the subject, such as to determine an evolution of the levelsof expression of the genes in the subject. The set of reference levelsof expression may be in the form of a database. The database may beincluded in a computer-readable medium. The database may be incommunications with a microprocessor and microprocessor instructions forproviding a user interface to receive expression level data of a subjectand to compare the expression level data with the database.

The invention also provides methods for determining the effectiveness ofa treatment intended to reduce bone or cartilage formation, comprising,e.g., obtaining a biological sample from the subject and comparing geneexpression levels in the biological sample to those of a set ofreference levels of expression during normal bone and cartilageformation, wherein significant differences in the levels of expressionof the plurality of genes indicates that the treatment is effective.

The methods of the invention may comprise obtaining a sample;identifying expression levels of a plurality of genes listed in Table 1,2, 5, 6 and/or 7 from the sample; determining whether the levels ofexpression of the genes in the patient sample are more similar to thoseof a cell differentiating into bone or cartilage or to those of aprecursor cell; and transmitting the results. The results may betransmitted across a network.

The invention also provides methods for identifying a compound fortreating a disease related to bone or cartilage formation, comprising,e.g., providing levels of expression of a plurality of genes listed inTable 1, 2, 5, 6 and/or 7 in a cell of a subject incubated with a testcompound; providing levels of expression of a cell differentiating intobone or cartilage; and comparing the two levels of expression, whereinsignificantly different levels of expression in the two cells indicatesthat the compound is likely to be effective for treating a diseaserelated to bone or cartilage formation. Also provided are methods foridentifying a compound for treating a disease related to bone orcartilage resorption, comprising, e.g., providing levels of expressionof a plurality of genes listed in Table 1, 2, 5, 6 and/or 7 in a cell ofa subject incubated with a test compound; providing levels of expressionof a cell differentiating into bone or cartilage; and comparing the twolevels of expression, wherein significantly similar levels of expressionin the two cells indicates that the compound is likely to be effectivefor treating a disease related to bone or cartilage formation.

In yet another embodiment, the invention provides a method foridentifying a compound that modulates bone or cartilage formation,comprising, e.g., contacting a precursor cell with an agent thatstimulates bone or cartilage formation and a test compound; anddetermining the level of expression of one or more genes of Tables 1, 2,6 and 7 during the bone or cartilage formation; wherein a significantsimilarity or difference between the expression level of the genes inthe cell and reference expression levels of the genes during bone orcartilage formation indicates that the test compound modulates bone orcartilage formation. The reference expression levels may be essentiallyidentical to the levels set forth in Table 1, 2, 5, 6 and/or 7. Othermethods for identifying a compound that stimulates bone or cartilageformation, comprises, e.g., contacting a precursor cell with a testcompound; and determining the level of expression of one or more genesof Tables 1, 2, 6 and 7 in the cell over time; wherein a similaritybetween the expression level of the genes in the cell and referenceexpression levels of the genes during bone or cartilage formationindicates that the test compound stimulates bone or cartilage formation.The reference expression levels may be levels set forth in Table 1, 2,5, 6 and/or 7.

Also provided are methods for identifying a compound that binds to apolypeptide encoded by a gene listed in Table 1, 2, 5, 6 and/or 7,comprising, e.g., contacting a polypeptide encoded by a gene listed inTable 1, 2, 5, 6 and/or 7 with a test compound under essentiallyphysiological conditions; and determining whether the compound binds tothe polypeptide. In another embodiment, the invention provides a methodfor identifying a compound that modulates a biological activity of apolypeptide encoded by a gene listed in Table 1, 2, 5, 6 and/or 7,comprising, e.g., contacting a polypeptide encoded by a gene listed inTable 1, 2, 5, 6 and/or 7 with a test compound under essentiallyphysiological conditions; and determining the biological activity of thepolypeptide, wherein a higher or lower biological activity of thepolypeptide in the presence of the test compound relative to the absenceof the test compound indicates that the test compound modulates thebiological activity of the polypeptide. The gene may be CLF-1 or MMP23.Other methods for identifying a compound for treating a disease relatedto bone or cartilage formation or resorption, comprise, e.g.,identifying a compound that modulates the activity of a polypeptideencoded by a gene listed in Table 1, 2, 6 or 7; and contacting aprecursor cell with the compound in the presence or absence of an agentthat stimulates the differentiation into bone or cartilage, whereinstimulation or inhibition of bone or cartilage formation from the cellindicates that the test compound is effective for treating a diseaserelated to bone or cartilage formation or resorption.

The invention also provides methods of treatment, e.g., methods fortreating a disease related to bone or cartilage formation or resorption,comprising administering to a subject having a disease related to boneor cartilage formation or resorption a compound that modulates thebiological activity of a polypeptide encoded by a gene listed in Table1, 2, 5, 6 and/or 7 and thereby modulates bone or cartilage formation,to thereby treat the disease in the subject.

Also within the scope of the invention are diagnostic or drug discoverykits, e.g., comprising a computer-readable medium, a composition a solidsurface as described herein, and optionally instructions for use.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a time course for BMP-2 induction of cytokine receptor-likefactor 1 expression (CLF-1) in a mouse model of ectopic bone formation.

FIG. 2 shows a time course for BMP-2 induction of matrixmetalloproteinase 23 expression (MMP23) in a mouse model of ectopic boneformation.

FIG. 3 shows time-dependent changes in the expression of selected markergenes of endochondral bone formation. FIG. 3A shows changes inexpression for Cyr61; FIG. 3B shows changes in expression for Col2a1;FIG. 3C shows changes in expression for Runx2; and FIG. 3D shows changesin expression for Ctsk.

BRIEF DESCRIPTION OF THE TABLES

Table 1 lists genes on the U74 microarrays for which BMP-2 induced atleast a two-fold increase in expression at any time point.

Table 2 lists genes on the U74 microarrays for which BMP-2 induced atleast a two-fold decrease in expression at any time point.

Table 3 summarizes the cells stained with an antisense riboprobe forCLF-1 mRNA.

Table 4 summarizes the cells stained with an antisense riboprobe forMMP23 mRNA.

Table 5 lists genes, previously associated with bone or cartilagemetabolism, on the Mu1a microarray for which BMP-2 induced at least afour-fold change in expression at any time point.

Table 6 lists genes, not associated with bone or cartilage metabolism,on the Mu1a microarray for which BMP-2 induced at least a four-foldchange in expression at any time point.

Table 7 lists genes from Tables 5 and 6 whose expression profilescorrelate with those of selected gene markers for processes contributingto bone formation.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based at least in part on the identification of geneswhich are up- and down-regulated during bone and cartilage formation, inparticular, during endochondral or ectopic bone formation. Genes whichare modulated include cell surface proteins, cytokines, extracellularmatrix proteins, extracellular proteins, intracellular proteins,proteases, receptors, signal transduction proteins and transcriptionfactors. In these expression profiles, certain genes are significantlyup-regulated, e.g., MMP23, CLF-1, cadherin 11, and CD68 antigen, andcertain genes are significantly down-regulated, e.g., vascularendothelial growth factor B and fatty acid synthase, duringdifferentiation. Tables 1 and 2 list genes which are modulated by afactor of at least about 2 and Tables 5 and 6 list genes which aremodulated by a factor of at least about 4. Genes of particular interestare indicated in italics and in bold in the Tables.

Whereas some of the genes listed in the Tables may have been known to bepotentially involved in bone and cartilage formation, many other geneslisted in the Tables have never before been associated with theseprocesses.

One of the genes not previously known to be associated with bone orcartilage formation that was found to be significantly up-regulated andthen down-regulated during the mesenchymal cell differentiation intobone and cartilage is Cytokine Receptor-Like Factor 1 (CLF-1 or CLRF-1,as in Table 6) (see, FIG. 1). Its up-regulation during bone formation isshown in FIG. 1. The mouse CLF-1 gene (also known as CRLM3 mRNA forcytokine receptor like molecule 3) is transcribed into a 1646 bp mRNA(SEQ ID NO: 1; GenBank Accession No. AB040038) which encodes a mouseprotein of 425 amino acids (GenBank Accession No. BAA92777) and a humanprotein of 422 amino acids. The nucleotide and amino acid sequences ofhuman CLF-1 are set forth as GenBank Accession Nos. NM_(—)004750 (SEQ IDNO: 1) and NP_(—)004741 (SEQ ID NO: 2) (Elson et al. (1998) J. Immunol.161:1371. Other human nucleotide sequences have GenBank Accession Nos.AX205046 and AF073515. Other human amino acid sequences have GenBankAccession Nos. AAD39681. The protein is secreted and dimerizes withcardiotrophin-like cytokine (CLC) (Elson et al. (2000) NatureNeuroscience 3(9): 867-872). This heterodimer is also a cytokine (Elson,et al. Nature Neuroscience 3(9):867-872, 2000). The CLC/CLF-1heterodimeric cytokine binds to ciliary neurotrophic factor receptor(CNTFR) (Elson, et al. Nature Neuroscience 3(9):867-872, 2000). Ligationof CNTFR activates STAT3 (Lelievre et al., J. Biol. Chem.276(25):22476-22484, 2001). STAT3 activation is tied to thedifferentiation of a number of cell types such as osteoblasts andosteoclasts. CLF-1 plays a role in promoting the differentiation ofmesenchymal progenitor cells towards either chondrocytes or osteoblasts.

Another gene that was not previously known to be associated with bone orcartilage formation that was found to be up- and then down-regulatedduring bone and cartilage formation is Matrix Metalloproteinase 23(MMP23) (see FIG. 2). Its upregulation during bone development is setforth in FIG. 2. The gene is transcribed into a mRNA of 1434 base pairs(GenBank Accession No. AF085742), which encodes a protein of 391 aminoacid (GenBank Accession No. AAC34886). The nucleotide and amino acidsequences of human MMP23 have GenBank Accession No. AJ005256 (SEQ ID NO:3) and CAB38176 (SEQ ID NO: 4) (Velasco et al. (1999) J. Biol. Chem.274:4570. The MMP23 protein is a secreted and also membrane boundprotease. Unlike other MMPs it is secreted as an active protease. MMP23plays a role in normal tissue remodeling (which is part of the boneformation) and in pathological erosion of extracellular matrix proteins(which is part of an arthritic disease).

In another aspect, the invention is based at least in part on theidentification of genes which are up- and down-regulated duringparticular phases of bone and cartilage formation. Table 7 containsgenes whose time-dependent expression profiles correlate with theprofiles of four phenotypic markers (Cyr61, Col2a 1, Runx2, and Ctsk) ofone or more phases of endochondral bone formation. Cyr61 is a member ofthe CCN family of growth factors and is believed to regulate theproliferation and differentiation of various connective tissue celltypes. Col2a1, Runx2 and Ctsk are well-defined markers for chondrocytes,osteoblasts and osteoclasts, respectively. Such genes may also bemarkers of bone formation phases, or have a functional connection to themarkers with whose expression they correlate.

Although at least some of the genes listed in Tables 1, 2, 5, 6 and/or 7may not be human genes, corresponding human genes are available or canbe obtained within undue experimentation by a person of skill in theart. Methods of the invention may use human or non-human genes,depending on the similarity between the two and the particular use ofthe genes. A person of skill in the art can determine whether a nucleicacid or protein of a human or non-human gene can be used.

1. DEFINITIONS

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofordinary skill in the art to which this invention belongs.

The singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise.

The phrase “a corresponding normal cell of” or “normal cellcorresponding to” or “normal counterpart cell of” a diseased cell refersto a normal cell of the same type as that of the diseased cell.

The term “agonist,” as used herein, is meant to refer to an agent thatmimics or up-regulates (e.g., potentiates or supplements) thebioactivity of a protein. An agonist can be a wild-type protein orderivative thereof having at least one bioactivity of the wild-typeprotein. An agonist can also be a compound that upregulates expressionof a gene or which increases at least one bioactivity of a protein. Anagonist can also be a compound which increases the interaction of apolypeptide with another molecule, e.g., a target peptide or nucleicacid.

“Antagonist” as used herein is meant to refer to an agent thatdownregulates (e.g., suppresses or inhibits) at least one bioactivity ofa protein. An antagonist can be a compound which inhibits or decreasesthe interaction between a protein and another molecule, e.g., a targetpeptide or enzyme substrate. An antagonist can also be a compound thatdown-regulates expression of a gene or which reduces the amount ofexpressed protein present.

By “array” or “matrix” is meant an arrangement of addressable locationsor “addresses” on a device. The locations can be arranged in twodimensional arrays, three dimensional arrays, or other matrix formats.The number of locations can range from several to at least hundreds ofthousands. Most importantly, each location represents a totallyindependent reaction site. A “nucleic acid array” refers to an arraycontaining nucleic acid probes, such as oligonucleotides or largerportions of genes. The nucleic acid on the array is preferably singlestranded. Arrays wherein the probes are oligonucleotides are referred toas “oligonucleotide arrays” or “oligonucleotide chips.” A “microarray,”also referred to herein as a “biochip” or “biological chip” is an arrayof regions having a density of discrete regions of at least about100/cm², and preferably at least about 1000/cm². The regions in amicroarray have typical dimensions, e.g., diameters, in the range ofbetween about 10-250 μm, and are separated from other regions in thearray by about the same distance.

The term “biological sample”, as used herein, refers to a sampleobtained from a subject, e.g., a human or from components (e.g.,tissues) of a subject. The sample may be of any biological tissue orfluid. Frequently the sample will be a “clinical sample” which is asample derived from a patient. Such samples include, but are not limitedto bodily fluids which may or may not contain cells, e.g., blood,synovial fluid; tissue or fine needle biopsy samples, such as from bone,cartilage or tissues containing mesenchymal cells. Biological samplesmay also include sections of tissues such as frozen sections taken forhistological purposes.

The term “biomarker” of a disease related to bone or cartilage formationor resorption refers to a gene which is up- or down-regulated in adiseased cell of a subject having such a disease, relative to acounterpart normal cell, which gene is sufficiently specific to thediseased cell that it can be used, optionally with other genes, toidentify or detect the disease. Generally, a biomarker is a gene that ischaracteristic of the disease.

“Bone formation” or “bone development” refers to ossification orosteogenesis, such as by endochondral bone formation or intramembraneousbone formation. In intramembraneous bone formation, osteogenesis occursdirectly in the condensed mesenchymal cells. In endochondralossification, mesenchymal cells first condense to form a cartilagemodel, and then bone formation occurs replacing the cartilage.Osteoprogenitor cells include mesenchymal and skeletal mesenchymalcells. Angiogenesis is part of bone formation. Thus, inhibiting orstimulating angiogenesis may inhibit or stimulate bone formation.

A “cell characteristic of a disease” also referred to as a “diseasedcell” refers to a cell of a subject having a disease, which cell isaffected by the disease, and is therefore different from thecorresponding cell in a non-diseased subject. A diseased cell can alsobe a cell that is present in significantly higher or lower numbers in asubject having the disease relative to a healthy subject. For example acell characteristic of cancer is a cancer cell or tumor cell. A diseasedcell may also differ from a normal cell in its gene expression profile.A disease cell of a disease relating to bone or cartilage formation orresorption can be a mesenchymal cell, a chondroblast, a chondrocyte, anosteoblast, an osteocyte, a fibroblast or other cells present in bone orcartilage or in bone or cartilage forming tissues.

A “cell sample characteristic of a disease” or a “tissue samplecharacteristic of a disease” refers to a sample of cells, such as atissue, that contains at least one cell characteristic of the disease.

A “computer readable medium” is any medium that can be used to storedata which can be accessed by a computer. Exemplary media include:magnetic storage media, such as a diskettes, hard drives, and magnetictape; optical storage media such as CD-ROMs; electrical storage mediasuch as RAM and ROM; and hybrids of these media, such asmagnetic/optical storage medium.

The term “derivative” refers to the chemical modification of a compound,e.g., a polypeptide, or a polynucleotide. Chemical modifications of apolynucleotide can include, for example, replacement of hydrogen by analkyl, acyl, or amino group. A derivative polynucleotide encodes apolypeptide which retains at least one biological or immunologicalfunction of the natural molecule. A derivative polypeptide can be onemodified by glycosylation, pegylation, or any similar process thatretains at least one biological or immunological function of thepolypeptide from which it was derived.

A disease, disorder, or condition “associated with” or “characterizedby” or “relating to bone or cartilage formation or resorption” refers toa disease, condition or disorder involving cells that are associatedwith bone or cartilage formation or resorption. Exemplary diseasesinclude osteodystrophy, osteohypertrophy, osteoblastoma, osteopertrusis,osteogenesis imperfecta, osteoporosis, osteopenia, osteoma andosteoblastoma; periodontal disease; hyperparathyroidism; hypercalcemiaof malignancy; Paget's disease; osteolytic lesions produced by bonemetastasis; bone loss due to immobilization or sex hormone deficiency;bone and cartilage loss cause by an inflammatory disease, e.g.,rheumatoid arthritis and osteoarthritis; wound healing and relatedtissue repair (e.g., burns, incisions and ulcers) and bone fractures. A“disease relating to bone or cartilage formation” refers to a disease,disorder or condition that can be treated by inhibiting bone orcartilage formation. A “disease relating to bone or cartilageresorption” refers to a disease, disorder or condition that can betreated by stimulating bone or cartilage formation.

A “detection agent of a gene” refers to an agent that can be used tospecifically detect a gene or other biological molecule relating to it,e.g., RNA transcribed from the gene and polypeptides encoded by thegene. Exemplary detection agents are nucleic acid probes which hybridizeto nucleic acids corresponding to the gene, polypeptide probes,polypeptides, such as antibodies, and small molecules.

The term “equivalent” is understood to include nucleotide sequencesencoding functionally equivalent polypeptides. Equivalent nucleotidesequences will include sequences that differ by one or more nucleotidesubstitutions, additions or deletions, such as allelic variants; andwill, therefore, include sequences that differ from the nucleotidesequence of the nucleic acids referred to in Any of Tables 1-5 due tothe degeneracy of the genetic code.

The term “expression profile,” which is used interchangeably herein with“gene expression profile,” “finger print” and “expression pattern”refers to a set of values representing the activity of about 10 or moregenes. An expression profile preferably comprises values representingexpression levels of at least about 20 genes, preferably at least about30, 50, 100, 200 or more genes.

“Genes that are up- or down-regulated” in a particular process, e.g.,bone and cartilage formation, refer to genes which are up- ordown-regulated by, e.g., a factor of at least about 1.1 fold, 1.25 fold,1.5 fold, 2 fold, 5 fold, 10 fold or more. Exemplary genes that are up-or down-regulated during bone and cartilage formation are set forth inTables 1, 2, 5, 6 and/or 7. “Genes that are up- or down-regulated in adisease” refer to the genes which are up- or down-regulated by, e.g., atleast about 1.1 fold, 1.25 fold, 1.5 fold, 2 fold, 5 fold, 10 fold ormore in at least about 50%, preferably 60%, 70%, 80%, or 90% of thepatients having the disease.

“Hybridization” refers to any process by which a strand of nucleic acidbinds with a complementary strand through base pairing. Twosingle-stranded nucleic acids “hybridize” when they form adouble-stranded duplex. The region of double-strandedness can includethe full-length of one or both of the single-stranded nucleic acids, orall of one single stranded nucleic acid and a subsequence of the othersingle stranded nucleic acid, or the region of double-strandedness caninclude a subsequence of each nucleic acid. Hybridization also includesthe formation of duplexes which contain certain mismatches, providedthat the two strands are still forming a double stranded helix.“Stringent hybridization conditions” refers to hybridization conditionsresulting in essentially specific hybridization.

The term “isolated” as used herein with respect to nucleic acids, suchas DNA or RNA, refers to molecules separated from other DNAs, or RNAs,respectively, that are present in the natural source of themacromolecule. The term isolated as used herein also refers to a nucleicacid or peptide that is substantially free of cellular material, viralmaterial, or culture medium when produced by recombinant DNA techniques,or chemical precursors or other chemicals when chemically synthesized.Moreover, an “isolated nucleic acid” is meant to include nucleic acidfragments which are not naturally occurring as fragments and would notbe found in the natural state. The term “isolated” is also used hereinto refer to polypeptides which are isolated from other cellular proteinsand is meant to encompass both purified and recombinant polypeptides.

As used herein, the terms “label” and “detectable label” refer to amolecule capable of detection, including, but not limited to,radioactive isotopes, fluorophores, chemiluminescent moieties, enzymes,enzyme substrates, enzyme cofactors, enzyme inhibitors, dyes, metalions, ligands (e.g., biotin or haptens) and the like. The term“fluorescer” refers to a substance or a portion thereof which is capableof exhibiting fluorescence in the detectable range. Particular examplesof labels which may be used under the invention include fluorescein,rhodamine, dansyl, umbelliferone, Texas red, luminol, NADPH,alpha-beta-galactosidase and horseradish peroxidase.

The “level of expression of a gene” refers to the activity of a gene,which can be indicated by the level of mRNA, as well as pre-mRNA nascenttranscript(s), transcript processing intermediates, mature mRNA(s) anddegradation products, and polypeptides encoded by the gene. Accordingly,the level of expression of a gene also refers to the amount ofpolypeptide encoded by the gene.

The phrase “normalizing expression of a gene” in a diseased cell refersto an action to compensate for the altered expression of the gene in thediseased cell, so that it is essentially expressed at the same level asin the corresponding non diseased cell. For example, where the gene isover-expressed in the diseased cell, normalization of its expression inthe diseased cell refers to treating the diseased cell in such a waythat its expression becomes essentially the same as the expression inthe counterpart normal cell. “Normalization” preferably brings the levelof expression to within approximately a 50% difference in expression,more preferably to within approximately a 25%, and even more preferably10% difference in expression. The required level of closeness inexpression will depend on the particular gene, and can be determined asdescribed herein. The phrase “normalizing gene expression in a diseasedcell” refers to an action to normalize the expression of a substantialnumber of genes in the diseased cell.

As used herein, the term “nucleic acid” refers to polynucleotides suchas deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid(RNA). The term should also be understood to include, as equivalents,analogs of either RNA or DNA made from nucleotide analogs, and, asapplicable to the embodiment being described, single (sense orantisense) and double-stranded polynucleotides. ESTs, chromosomes,cDNAs, mRNAs, and rRNAs are representative examples of molecules thatmay be referred to as nucleic acids.

The phrase “nucleic acid corresponding to a gene” refers to a nucleicacid that can be used for detecting the gene, e.g., a nucleic acid whichis capable of hybridizing specifically to the gene.

The term “percent identical” refers to sequence identity between twoamino acid sequences or between two nucleotide sequences. Identity caneach be determined by comparing a position in each sequence which may bealigned for purposes of comparison. When an equivalent position in thecompared sequences is occupied by the same base or amino acid, then themolecules are identical at that position; when the equivalent siteoccupied by the same or a similar amino acid residue (e.g., similar insteric and/or electronic nature), then the molecules can be referred toas homologous (similar) at that position. Expression as a percentage ofhomology, similarity, or identity refers to a function of the number ofidentical or similar amino acids at positions shared by the comparedsequences. Various alignment algorithms and/or programs may be used,including FASTA, BLAST, or ENTREZ. FASTA and BLAST are available as apart of the GCG sequence analysis package (University of Wisconsin,Madison, Wis.), and can be used with, e.g., default settings. ENTREZ isavailable through the National Center for Biotechnology Information,National Library of Medicine, National Institutes of Health, Bethesda,Md. In one embodiment, the percent identity of two sequences can bedetermined by the GCG program with a gap weight of 1, e.g., each aminoacid gap is weighted as if it were a single amino acid or nucleotidemismatch between the two sequences. Other techniques for alignment aredescribed in Methods in Enzymology, vol. 266: Computer Methods forMacromolecular Sequence Analysis (1996), ed. Doolittle, Academic Press,Inc., a division of Harcourt Brace & Co., San Diego, Calif., USA.Preferably, an alignment program that permits gaps in the sequence isutilized to align the sequences. The Smith-Waterman is one type ofalgorithm that permits gaps in sequence alignments. See Meth. Mol. Biol.70: 173-187 (1997). Also, the GAP program using the Needleman and Wunschalignment method can be utilized to align sequences. An alternativesearch strategy uses MPSRCH software, which runs on a MASPAR computer.MPSRCH uses a Smith-Waterman algorithm to score sequences on a massivelyparallel computer. This approach improves ability to pick up distantlyrelated matches, and is especially tolerant of small gaps and nucleotidesequence errors. Nucleic acid-encoded amino acid sequences can be usedto search both protein and DNA databases. Databases with individualsequences are described in Methods in Enzymology, ed. Doolittle, supra.Databases include Genbank, EMBL, and DNA Database of Japan (DDBJ).

“Perfectly matched” in reference to a duplex means that the poly- oroligonucleotide strands making up the duplex form a double strandedstructure with one other such that every nucleotide in each strandundergoes Watson-Crick basepairing with a nucleotide in the otherstrand. The term also comprehends the pairing of nucleoside analogs,such as deoxyinosine, nucleosides with 2-aminopurine bases, and thelike, that may be employed. A mismatch in a duplex between a targetpolynucleotide and an oligonucleotide or olynucleotide means that a pairof nucleotides in the duplex fails to undergo Watson-Crick bonding. Inreference to a triplex, the term means that the triplex consists of aperfectly matched duplex and a third strand in which every nucleotideundergoes Hoogsteen or reverse Hoogsteen association with a basepair ofthe perfectly matched duplex.

A “plurality” refers to two or more.

A “precursor cell”, or “progenitor cell”, refers to a cell that has thecapacity to create progeny that are more differentiated than itself. Forexample, the term may refer to an undifferentiated cell or celldifferentiated to an extent short of final differentiation which iscapable of proliferation and giving rise to more progenitor cells havingthe ability to generate a large number of mother cells that can in turngive rise to differentiated, or differentiable daughter cells. Incertain embodiments, the term progenitor cell refers to a generalizedmother cell whose descendants (progeny) specialize, often in differentdirections, by differentiation, e.g., by acquiring completely individualcharacters, as occurs in progressive diversification of embryonic cellsand tissues. Cellular differentiation is a complex process typicallyoccurring through many cell divisions. A differentiated cell may derivefrom a multipotent cell which itself is derived from a multipotent cell,and so on. While each of these multipotent cells may be considered stemcells, the range of cell types each can give rise to may varyconsiderably. Some differentiated cells also have the capacity to giverise to cells of greater developmental potential. Such capacity may benatural or may be induced artificially upon treatment with variousfactors. By this definition, stem cells may also be progenitor cells, aswell as the more immediate precursors to terminally differentiatedcells. Exemplary precursor cells involved in bone and cartilageformation include osteoprogenitor cells such as for example mesenchymalprecursors cells, osteoblasts, and chondroblasts. As used herein, anucleic acid or other molecule attached to an array, is referred to as a“probe” or “capture probe.” When an array contains several probescorresponding to one gene, these probes are referred to as “gene-probeset.” A gene-probe set can consist of, e.g., 2 to 10 probes, preferablyfrom 2 to 5 probes and most preferably about 5 probes.

A “significant similarity” between the level of expression of a gene intwo cells or tissues generally refers to a difference in expressionlevels of a factor of at most about 10% (i.e., 1.1 fold), 25% (i.e.,1.25 fold), 50% (i.e., 1.5 fold), 75% (i.e., 1.75 fold), 90% (i.e., 1.9fold), 2 fold, 2.5 fold, 3 fold, 5 fold, or 10 fold. Expression levelscan be raw data or they can averaged or normalized data, e.g.,normalized relative to normal controls. A “significant difference”between the level of expression of a gene in two cells or tissuesgenerally refers to a difference in expression levels of a factor of atleast about 10% (i.e., 1.1 fold), 25% (i.e., 1.25 fold), 50% (i.e., 1.5fold), 75% (i.e., 1.75 fold), 90% (i.e., 1.9 fold), 2 fold, 2.5 fold, 3fold, 5 fold, 10 fold, 50 fold or 100 fold. Whether the expression of aparticular gene in two samples is significantly different or similaralso depends on the gene itself and, e.g., its variability in expressionbetween different individuals. It is within the skill in the art todetermine whether expression levels are significantly similar ordifferent.

An expression profile in one cell or tissue is “significantly similar”to an expression profile in another cell or tissue when the level ofexpression of the genes in the two expression profiles are sufficientlysimilar that the similarity is indicative of a common characteristic,e.g., being of the same cell type, or being characteristic of a disease.“Similarity” between an expression profile of a cell or tissue, e.g., ofa subject, and a set of data representing an expression profilecharacteristic of a disease can be based on the presence or absence inthe cell or tissue of certain RNAs and/or certain levels of certain RNAsof genes having a high probability of being associated with the disease.A high probability of being associated with a disease can be, e.g., thepresence of RNA or of certain levels of RNA of particular genes whichare over-expressed or under-expressed, in at least about 50%, 60%, 70%,80%, 90%, or 100% of patients having the disease. A similarity with anexpression profile of a patient can be based on higher or lowerexpression levels of a factor of at most about 10%, 25%, 50%, 75%, 1.5fold, 2 fold, 2.5 fold, 3 fold, 5 fold or 10 fold of at least about 50%,60%, 70%, 80%, 90%, or 100% of genes, or at least about 10, 50, 100,200, 300 genes, that are up- or down-regulated in at least about 50%,60%, 70%, 80%, 0.90%, or 100% of patients.

“Small molecule” as used herein, is meant to refer to a composition,which has a molecular weight of less than about 5 kD and most preferablyless than about 4 kD. Small molecules can be nucleic acids, peptides,polypeptides, peptidomimetics, carbohydrates, lipids or other organic(carbon-containing) or inorganic molecules. Many pharmaceuticalcompanies have extensive libraries of chemical and/or biologicalmixtures, often fungal, bacterial, or algal extracts, which can bescreened with any of the assays of the invention to identify compoundsthat modulate a bioactivity.

The term “specific hybridization” of a probe to a target site of atemplate nucleic acid refers to hybridization of the probe predominantlyto the target, such that the hybridization signal can be clearlyinterpreted. As further described herein, such conditions resulting inspecific hybridization vary depending on the length of the region ofhomology, the GC content of the region, the melting temperature “Tm” ofthe hybrid. Hybridization conditions will thus vary in the salt content,acidity, and temperature of the hybridization solution and the washes.

A “subject” can be a mammal, e.g., a human, primate, ovine, bovine,porcine, equine, feline, canine and a rodent (rat or mouse).

The term “treating” a disease in a subject or “treating” a subjecthaving a disease refers to providing the subject with a pharmaceuticaltreatment, e.g., the administration of a drug, such that at least onesymptom of the disease is decreased. Treating a disease can bepreventing the disease, improving the disease or curing the disease.

The phrase “value representing the level of expression of a gene” refersto a raw number which reflects the mRNA or polypeptide level of aparticular gene in a cell or biological sample, e.g., obtained fromanalytical tools for measuring RNA or polypeptide levels.

A “variant” of a polypeptide refers to a polypeptide having the aminoacid sequence of the polypeptide, in which one or more amino acidresidues are altered. The variant may have “conservative” changes,wherein a substituted amino acid has similar structural or chemicalproperties (e.g., replacement of leucine with isoleucine). More rarely,a variant may have “non-conservative” changes (e.g., replacement ofglycine with tryptophan). Analogous minor variations may also includeamino acid deletions or insertions, or both. Guidance in determiningwhich amino acid residues may be substituted, inserted, or deletedwithout abolishing biological or immunological activity may be foundusing computer programs well known in the art, for example, LASERGENEsoftware (DNASTAR). The term “variant,” when used in the context of apolynucleotide sequence, encompasses a polynucleotide sequence relatedto that of a gene of interest or the coding sequence thereof. Thisdefinition may also include, for example, “allelic,” “splice,”“species,” or “polymorphic” variants. A splice variant may havesignificant identity to a reference molecule, but will generally have agreater or lesser number of polynucleotides due to alternate splicing ofexons during mRNA processing. The corresponding polypeptide may possessadditional functional domains or an absence of domains. Species variantsare polynucleotide sequences that vary from one species to another. Theresulting polypeptides generally will have significant amino acididentity relative to each other. A polymorphic variant is a variation inthe polynucleotide sequence of a particular gene between individuals ofa given species. Polymorphic variants also may encompass “singlenucleotide polymorphisms” (SNPs) in which the polynucleotide sequencevaries by one base. The presence of SNPs may be indicative of, forexample, a certain population, a disease state, or a propensity for adisease state.

2. DIAGNOSTIC AND PROGNOSTIC METHODS AND COMPOSITIONS

The invention provides gene expression profiles over time during boneformation, e.g., endochondral bone formation induced by BMP-2. Sincethese expression profiles are characteristic of bone and cartilageformation, measuring the level of expression or level of product of oneor more genes identified in these expression profiles, e.g., genes setforth in Tables 1, 2, 5, 6 and/or 7, during bone or cartilage formationis expected to reveal any abnormalities in these processes.Abnormalities can then be treated appropriately, such as describedbelow.

Exemplary situations in which one may wish to monitor bone or cartilageformation or resorption include diseases relating to bone or cartilageformation or bone or cartilage resorption, such as osteodystrophy,osteohypertrophy, osteoblastoma, osteopertrusis, osteogenesisimperfecta, osteoporosis, osteopenia, osteoma and osteoblastoma;periodontal disease; hyperparathyroidism; hypercalcemia of malignancy;Paget's disease; osteolytic lesions produced by bone metastasis; boneloss due to immobilization or sex hormone deficiency; bone and cartilageloss cause by an inflammatory disease, e.g., rheumatoid arthritis andosteoarthritis; wound healing and related tissue repair (e.g., burns,incisions and ulcers) and bone fractures. Bone or cartilage formation orresorption can also be monitored during treatment of any of theabove-mentioned diseases and any conditions in which bone or cartilageformation is induced, such as by therapeutics, e.g., bone morphogeneticproteins. Situations in which bone or cartilage formation may be inducedinclude healing of fractures, e.g., in closed and open fracturereduction; improved fixation of artificial joints; repair of congenital,trauma induced, or oncologic resection induced craniofacial defects;tooth repair processes and plastic, e.g., cosmetic plastic, surgery.

Accordingly, the invention provides methods for diagnosing andmonitoring the development of any disease relating to bone or cartilageformation or resorption, such as the diseases set forth above. Themethods of the invention also allow to distinguish one disease fromanother, where such distinction is not possible based on phenotypic orhistologic examination.

In yet another embodiment, the methods of the invention allow thedetermination of the stage of a particular disease. For example, byknowing the level of expression of certain genes, the state of bone orcartilage development can be established.

The methods of the invention can also be used to monitor the treatmentof a disease. Monitoring will reveal whether a subject is responsive toa treatment or whether the treatment should be modified.

Measuring the level of expression or the level of product of one or moregenes described herein can also be used in prognostics, such as todetermine whether a subject is likely to develop a disease relating tobone or cartilage formation or resorption. For example a subject whosefamily is associated with such disorders can be monitored to determinewhether he or she will develop such a disorder.

Another situation during which gene expression can be monitored isduring in vitro bone or cartilage formation, e.g., induced by a bonemorphogenetic protein. In vitro synthesized bone or cartilage can beused for implanting into subject in need thereof, such as subjectshaving suffered bone loss, e.g., resulting from cancer or osteoporosis.

In one embodiment, a sample is obtained from a subject, e.g., a humansubject, and the level of expression of one or more genes, such as geneslisted in any of Tables 1, 2, 5, 6 and/or 7, is determined. Theparticular method used for obtaining a sample will depend on the site ofthe sample to be obtained. Samples can be obtained according to methodsknown in the art. As few as one cell may be sufficient for determininggene expression. In other embodiments, the presence of proteins isdetermined in a bodily fluid, e.g., blood or synovial fluid. Geneexpression can be determined according to methods known in the art, suchas reverse transcriptase polymerase chain reaction (RT-PCR); nucleicacid arrays; dotblots; and in situ hybridization, as further describedherein. In other embodiments, the level of protein is measured, such asby immunohistochemistry, ELISA, or immunoprecipitation.

In certain embodiments, several samples are obtained consecutively, anda change of expression is monitored over time. For example, samples maybe obtained about every 1, 2, 3, 5, 6, 12, 24, 36 or 48 hours.

The level of expression of one or more genes in a sample can be comparedto the level of expression of these genes in a control sample. A controlsample may be obtained, e.g., from the same patient, but at a differentsite, or from a healthy subject. Alternatively, the level of expressionof the genes in the sample is compared to values stored in adata-readable medium, such as the values set forth in Tables 1, 2, 5, 6and/or 7 or in FIG. 1 or 2 or 3. The comparison can be conductedvisually, or via a computer.

The presence of a bone or cartilage related disease or a defect in thetreatment of such a disease may be indicated by differences in the levelof expression of one or more genes in a sample and in the controlsample. The differences in gene expression may be a difference of afactor of at least about 50%; 2; 3; 5; 10; 20; 50; or 100 fold. In otherembodiments, an abnormality is revealed by comparing the level ofexpression of one or more genes over time with their expression in acontrol or healthy subject.

The diagnostic and prognostic assays may indicate a defect in cartilageor bone formation or the existence of inefficient treatment of a diseaseor healing, e.g., bone fracture healing. The assays may thus be followedby a proper treatment or correction of treatment. Exemplary treatmentsare provided below. Generally, any therapeutic known to correct thediagnosed abnormality can be used. For example, defective bone orcartilage formation may be corrected by administration of a bonemorphogenetic protein (BMP), e.g., BPM-2 or BMP-4.

2.1. Use of Arrays for Determining the Level of Expression of Genes

Generally, determining expression profiles with arrays involves thefollowing steps: (a) obtaining a mRNA sample from a subject andpreparing labeled nucleic acids therefrom (the “target nucleic acids” or“targets”); (b) contacting the target nucleic acids with the array underconditions sufficient for target nucleic acids to bind withcorresponding probes on the array, e.g. by hybridization or specificbinding; (c) optionally removing unbound targets from the array; (d)detecting bound targets, and (e) analyzing the results. As used herein,“nucleic acid probes” or “probes” are nucleic acids attached to thearray, whereas “target nucleic acids” are nucleic acids that arehybridized to the array. Each of these steps is described in more detailbelow.

(i) Obtaining a mRNA Sample of a Subject

In one embodiment, one or more cells from the subject to be tested areobtained and RNA is isolated from the cells. In a preferred embodiment,a sample of bone, cartilage, mesenchymal cells, synovial fluid,synovium, tumor or other tissue likely to be affected by the disorder tobe diagnosed or monitored, are obtained from the subject according tomethods known in the art. Cells from which expression levels may beobtained include macrophages, fibroblasts, chondrocyte-like cells,chondrocytes, chondroblasts, bone marrow cells, osteoblast, osteocytes,osteoclasts, and osteogenic precursor cells, e.g., mesenchymal cells.When obtaining the cells, it is preferable to obtain a sample containingpredominantly cells of the desired type, e.g., a sample of cells inwhich at least about 50%, preferably at least about 60%, even morepreferably at least about 70%, 80% and even more preferably, at leastabout 90% of the cells are of the desired type. A higher percentage ofcells of the desired type is preferable, since such a sample is morelikely to provide clear gene expression data.

It is also possible to obtain a cell sample from a subject, and then toenrich it for a desired cell type. Cells can also be isolated from othercells using a variety of techniques, such as isolation with an antibodybinding to an epitope on the cell surface of the desired cell type.Another method that can be used includes negative selection usingantibodies to cell surface markers to selectively enrich for a specificcell type without activating the cell by receptor engagement. Where thedesired cells are in a solid tissue, particular cells can be dissectedout, e.g., by microdissection. Exemplary cells that one may want toenrich for include mesenchymal cells, such as muscular mesenchymalcells, osteoblasts, osteocytes, chondroblasts, chondrocytes, tumor cellsand other bone or cartilage cells.

In one embodiment, RNA is obtained from a single cell. For example, acell can be isolated from a tissue sample by laser capturemicrodissection (LCM). Using this technique, a cell can be isolated froma tissue section, including a stained tissue section, thereby assuringthat the desired cell is isolated (see, e.g., Bonner et al. (1997)Science 278: 1481; Emmert-Buck et al. (1996) Science 274:998; Fend etal. (1999) Am. J. Path. 154: 61 and Murakami et al. (2000) Kidney Int.58:1346). For example, Murakami et al., supra, describe isolation of acell from a previously immunostained tissue section.

It is also be possible to obtain cells from a subject and culture thecells in vitro, such as to obtain a larger population of cells fromwhich RNA can be extracted. Methods for establishing cultures ofnon-transformed cells, i.e., primary cell cultures, are known in theart.

When isolating RNA from tissue samples or cells from individuals, it maybe important to prevent any further changes in gene expression after thetissue or cells has been removed from the subject. Changes in expressionlevels are known to change rapidly following perturbations, e.g., heatshock or activation with lipopolysaccharide (LPS) or other reagents. Inaddition, the RNA in the tissue and cells may quickly become degraded.Accordingly, in a preferred embodiment, the tissue or cells obtainedfrom a subject is snap frozen as soon as possible.

RNA can be extracted from the tissue sample by a variety of methods,e.g., those described in the Examples or guanidium thiocyanate lysisfollowed by CsCl centrifugation (Chirgwin et al., 1979, Biochemistry18:5294-5299). RNA from single cells can be obtained as described inmethods for preparing cDNA libraries from single cells, such as thosedescribed in Dulac, C. (1998) Curr. Top. Dev. Biol. 36, 245 and Jena etal. (1996) J. Immunol. Methods 190:199. Care to avoid RNA degradationmust be taken, e.g., by inclusion of RNAsin.

The RNA sample can then be enriched in particular species. In oneembodiment, poly(A)+ RNA is isolated from the RNA sample. In general,such purification takes advantage of the poly-A tails on mRNA. Inparticular and as noted above, poly-T oligonucleotides may beimmobilized on a solid support to serve as affinity ligands for mRNA.Kits for this purpose are commercially available, e.g., the MessageMakerkit (Life Technologies, Grand Island, N.Y.).

In a preferred embodiment, the RNA population is enriched in sequencesof interest, such as those of genes listed in Tables 1, 2, 5, 6 and/or7. Enrichment can be undertaken, e.g., by primer-specific cDNAsynthesis, or multiple rounds of linear amplification based on cDNAsynthesis and template-directed in vitro transcription (see, e.g., Wanget al. (1989) PNAS 86, 9717; Dulac et al., supra, and Jena et al.,supra).

The population of RNA, enriched or not in particular species orsequences, can further be amplified. Such amplification is particularlyimportant when using RNA from a single or a few cells. A variety ofamplification methods are suitable for use in the methods of theinvention, including, e.g., PCR; ligase chain reaction (LCR) (See, e.g.,Wu and Wallace, Genomics 4, 560 (1989), Landegren et al., Science 241,1077 (1988)); self-sustained sequence replication (SSR) (see, e.g.,Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990)); nucleicacid based sequence amplification (NASBA) and transcriptionamplification (see, e.g., Kwoh et al., Proc. Natl. Acad. Sci. USA 86,1173 (1989)). For PCR technology, see, e.g., PCR Technology: Principlesand Applications for DNA Amplification (ed. H. A. Erlich, Freeman Press,N.Y., N.Y., 1992); PCR Protocols: A Guide to Methods and applications(eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattilaet al., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methodsand Applications 1, 17 (1991); PCR (eds. McPherson et al., IRL Press,Oxford); and U.S. Pat. No. 4,683,202. Methods of amplification aredescribed, e.g., in Ohyama et al. (2000) BioTechniques 29:530; Luo etal. (1999) Nat. Med. 5, 117; Hegde et al. (2000) BioTechniques 29:548;Kacharmina et al. (1999) Meth. Enzymol. 303:3; Livesey et al. (2000)Curr. Biol. 10:301; Spirin et al. (1999) Invest. Ophtalmol. Vis. Sci.40:3108; and Sakai et al. (2000) Anal. Biochem. 287:32. RNAamplification and cDNA synthesis can also be conducted in cells in situ(see, e.g., Eberwine et al. (1992) PNAS 89:3010).

One of skill in the art will appreciate that whatever amplificationmethod is used, if a quantitative result is desired, care must be takento use a method that maintains or controls for the relative frequenciesof the amplified nucleic acids to achieve quantitative amplification.Methods of “quantitative” amplification are well known to those of skillin the art. For example, quantitative PCR involves simultaneouslyco-amplifying a known quantity of a control sequence using the sameprimers. This provides an internal standard that may be used tocalibrate the PCR reaction. A high density array may then include probesspecific to the internal standard for quantification of the amplifiednucleic acid.

One preferred internal standard is a synthetic AW106 cRNA. The AW106ERNA is combined with RNA isolated from the sample according to standardtechniques known to those of skilled in the art. The RNA is then reversetranscribed using a reverse transcriptase to provide copy DNA. The cDNAsequences are then amplified (e.g., by PCR) using labeled primers. Theamplification products are separated, typically by electrophoresis, andthe amount of radioactivity (proportional to the amount of amplifiedproduct) is determined. The amount of mRNA in the sample is thencalculated by comparison with the signal produced by the known AW106 RNAstandard. Detailed protocols for quantitative PCR are provided in PCRProtocols, A Guide to Methods and Applications, Innis et al., AcademicPress, Inc. N.Y., (1990).

In a preferred embodiment, a sample mRNA is reverse transcribed with areverse transcriptase and a primer consisting of oligo(dT) and asequence encoding the phage T7 promoter to provide single stranded DNAtemplate. The second DNA strand is polymerized using a DNA polymerase.After synthesis of double-stranded cDNA, T7 RNA polymerase is added andRNA is transcribed from the cDNA template. Successive rounds oftranscription from each single cDNA template results in amplified RNA.Methods of in vitro polymerization are well known to those of skill inthe art (See, e.g., Sambrook, (supra) and this particular method isdescribed in detail by Van Gelder, et al., Proc. Natl. Acad. Sci. USA,87: 1663-1667 (1990) who demonstrate that in vitro amplificationaccording to this method preserves the relative frequencies of thevarious RNA transcripts). Moreover, Eberwine et al. Proc. Natl. Acad.Sci. USA, 89: 3010-3014 provide a protocol that uses two rounds ofamplification via in vitro transcription to achieve greater than 10⁶fold amplification of the original starting material, thereby permittingexpression monitoring even where biological samples are limited.

It will be appreciated by one of skill in the art that the directtranscription method described above provides an antisense (aRNA) pool.Where antisense RNA is used as the target nucleic acid, theoligonucleotide probes provided in the array are chosen to becomplementary to subsequences of the antisense nucleic acids.Conversely, where the target nucleic acid pool is a pool of sensenucleic acids, the oligonucleotide probes are selected to becomplementary to subsequences of the sense nucleic acids. Finally, wherethe nucleic acid pool is double stranded, the probes may be of eithersense as the target nucleic acids include both sense and antisensestrands.

(ii) Labeling of the Nucleic Acids to be Analyzed

Generally, the target molecules will be labeled to permit detection ofhybridization of target molecules to a microarray. By “labeled” is meantthat the probe comprises a member of a signal producing system and isthus detectable, either directly or through combined action with one ormore additional members of a signal producing system. Examples ofdirectly detectable labels include isotopic and fluorescent moietiesincorporated into, usually covalently bonded to, a moiety of the probe,such as a nucleotide monomeric unit, e.g. dNMP of the primer, or aphotoactive or chemically active derivative of a detectable label whichcan be bound to a functional moiety of the probe molecule.

Nucleic acids can be labeled after or during enrichment and/oramplification of RNAs. For example, labeled cDNA can be prepared frommRNA by oligo dT-primed or random-primed reverse transcription, both ofwhich are well known in the art (see, e.g., Klug and Berger, 1987,Methods Enzymol. 152:316-325). Reverse transcription may be carried outin the presence of a dNTP conjugated to a detectable label, mostpreferably a fluorescently labeled dNTP. Alternatively, isolated mRNAcan be converted to labeled antisense RNA synthesized by in vitrotranscription of double-stranded cDNA in the presence of labeled dNTPs(Lockhart et al., 1996, Expression monitoring by hybridization tohigh-density oligonucleotide arrays, Nature Biotech. 14:1675). Inalternative embodiments, the cDNA or RNA probe can be synthesized in theabsence of detectable label and may be labeled subsequently, e.g., byincorporating biotinylated dNTPs or rNTP, or some similar means (e.g.,photo-cross-linking a psoralen derivative of biotin to RNAs), followedby addition of labeled streptavidin (e.g., phycoerythrin-conjugatedstreptavidin) or the equivalent.

In one embodiment, labeled cDNA is synthesized by incubating a mixturecontaining RNA and 0.5 mM dGTP, dATP and dCTP plus 0.1 mM dTTP plusfluorescent deoxyribonucleotides (e.g., 0.1 mM Rhodamine 110 UTP (PerkenElmer Cetus) or 0.1 mM Cy3 dUTP (Amersham)) with reverse transcriptase(e.g., SuperScript™II, LTI Inc.) at 42° C. for 60 mm.

Fluorescent moieties or labels of interest include coumarin and itsderivatives, e.g. 7-amino-4-methylcoumarin, aminocoumarin, bodipy dyes,such as Bodipy FL, cascade blue, fluorescein and its derivatives, e.g.fluorescein isothiocyanate, Oregon green, rhodamine dyes, e.g. Texasred, tetramethylrhodamine, eosins and erythrosins, cyanine dyes, e.g.Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Fluor X, macrocyclic chelates oflanthanide ions, e.g. Quantum Dye™, fluorescent energy transfer dyes,such as thiazole orange-ethidium heterodimer, TOTAB, dansyl, etc.Individual fluorescent compounds which have functionalities for linkingto an element desirably detected in an apparatus or assay of theinvention, or which can be modified to incorporate such functionalitiesinclude, e.g., dansyl chloride; fluoresceins such as3,6-dihydroxy-9-phenylxanthydrol; rhodamineisothiocyanate; N-phenyl1-amino-8-sulfonatonaphthalene; N-phenyl 2-amino-6-sulfonatonaphthalene;4-acetamido-4-isothiocyanato-stilbene-2,2′-disulfonic acid;pyrene-3-sulfonic acid; 2-toluidinonaphthalene-6-sulfonate;N-phenyl-N-methyl-2-aminonaphthalene-6-sulfonate; ethidium bromide;stebrine; auromine-0,2-(9′-anthryl)palmitate; dansylphosphatidylethanolamine; N,N′-dioctadecyl oxacarbocyanine: N,N′-dihexyloxacarbocyanine; merocyanine, 4-(3′-pyrenyl)stearate;d-3-aminodesoxy-equilenin; 12-(9′-anthroyl)stearate; 2-methylanthracene;9-vinylanthracene; 2,2′(vinylene-p-phenylene)bisbenzoxazole;p-bis(2-methyl-5-phenyl-oxazolyl))benzene;6-dimethylamino-1,2-benzophenazin; retinol; bis(3′-aminopyridinium)1,10-decanediyl diiodide; sulfonaphthylhydrazone of hellibrienin;chlorotetracycline;N-(7-dimethylamino-4-methyl-2-oxo-3-chromenyl)maleimide;N-(p-(2-benzimidazolyl)-phenyl)maleimide; N-(4-fluoranthyl)maleimide;bis(homovanillic acid); resazarin;4-chloro-7-nitro-2,1,3-benzooxadiazole; merocyanine 540; resorufin; rosebengal; and 2,4-diphenyl-3(2H)-furanone. (see, e.g., Kricka, 1992,Nonisotopic DNA Probe Techniques, Academic Press San Diego, Calif.).Many fluorescent tags are commercially available from SIGMA chemicalcompany (Saint Louis, Mo.), Amersham, Molecular Probes, R&D systems(Minneapolis, Minn.), Pharmacia LKB Biotechnology (Piscataway, N.J.),CLONTECH Laboratories, Inc. (Palo Alto, Calif.), Chem Genes Corp.,Aldrich Chemical Company (Milwaukee, Wis.), Glen Research, Inc., GIBCOBRL Life Technologies, Inc. (Gaithersburg, Md.), FlukaChemica-Biochemika Analytika (Fluka Chemie AG, Buchs, Switzerland), andApplied Biosystems (Foster City, Calif.) as well as other commercialsources known to one of skill.

Chemiluminescent labels include luciferin and2,3-dihydrophthalazinediones, e.g., luminol.

Isotopic moieties or labels of interest include ³²P, ³³P, ³⁵S, ¹²⁵I, ²H,¹⁴C, and the like (see Zhao et al., 1995, High density cDNA filteranalysis: a novel approach for large-scale, quantitative analysis ofgene expression, Gene 156:207; Pietu et al., 1996, Novel genetranscripts preferentially expressed in human muscles revealed byquantitative hybridization of a high density cDNA array, Genome Res.6:492).

Labels may also be members of a signal producing system that act inconcert with one or more additional members of the same system toprovide a detectable signal. Illustrative of such labels are members ofa specific binding pair, such as ligands, e.g. biotin, fluorescein,digoxigenin, antigen, polyvalent cations, chelator groups and the like,where the members specifically bind to additional members of the signalproducing system, where the additional members provide a detectablesignal either directly or indirectly, e.g. antibody conjugated to afluorescent moiety or an enzymatic moiety capable of converting asubstrate to a chromogenic product, e.g. alkaline phosphatase conjugateantibody and the like.

Additional labels of interest include those that provide for signal onlywhen the probe with which they are associated is specifically bound to atarget molecule, where such labels include: “molecular beacons” asdescribed in Tyagi & Kramer, Nature Biotechnology (1996) 14:303 and EP 0070 685 B1. Other labels of interest include those described in U.S.Pat. No. 5,563,037; WO 97/17471 and WO 97/17076.

In some cases, hybridized target nucleic acids may be labeled followinghybridization. For example, where biotin labeled dNTPs are used in,e.g., amplification or transcription, streptavidin linked reportergroups may be used to label hybridized complexes.

In other embodiments, the target nucleic acid is not labeled. In thiscase, hybridization can be determined, e.g., by plasmon resonance, asdescribed, e.g., in Thiel et al. (1997) Anal. Chem. 69:4948.

In one embodiment, a plurality (e.g., 2, 3, 4, 5 or more) of sets oftarget nucleic acids are labeled and used in one hybridization reaction(“multiplex” analysis). For example, one set of nucleic acids maycorrespond to RNA from one cell or tissue sample and another set ofnucleic acids may correspond to RNA from another cell or tissue sample.The plurality of sets of nucleic acids can be labeled with differentlabels, e.g., different fluorescent labels which have distinct emissionspectra so that they can be distinguished. The sets can then be mixedand hybridized simultaneously to one microarray.

For example, the two different cells can be a cell of a subjectsuspected of having a disease related to bone or cartilage formation orresorption and a counterpart normal cell. In another embodiment, e.g.,for identifying drugs modulating bone formation, one biological samplecontains cells that were exposed to a drug and the other biologicalsample contains cells that were not exposed to the drug. The cDNAderived from each of the two cell types are differently labeled so thatthey can be distinguished. In one embodiment, for example, cDNA from onesample is synthesized using a fluorescein-labeled dNTP, and cDNA fromthe second sample is synthesized using a rhodamine-labeled dNTP. Whenthe two cDNAs are mixed and hybridized to the microarray, the relativeintensity of signal from each cDNA set is determined for each site onthe array, and any relative difference in abundance of a particular mRNAdetected.

In the example described above, the cDNA from one sample will fluorescegreen when the fluorophore is stimulated and the cDNA from the secondsample will fluoresce red. As a result, if the two cells are essentiallythe same, the particular mRNA will be equally prevalent in both cellsand, upon reverse transcription, red-labeled and green-labeled cDNA willbe equally prevalent. When hybridized to the microarray, the bindingsite(s) for that species of RNA will emit wavelengths characteristic ofboth fluorophores (and appear brown in combination). In contrast, if thetwo cells are different, the ratio of green to red fluorescence will bedifferent.

The use of a two-color fluorescence labeling and detection scheme todefine alterations in gene expression has been described, e.g., in Shenaet al., 1995, Quantitative monitoring of gene expression patterns with acomplementary DNA microarray, Science 270:467-470. An advantage of usingcDNA labeled with two different fluorophores is that a direct andinternally controlled comparison of the mRNA levels corresponding toeach arrayed gene in two cell states can be made, and variations due tominor differences in experimental conditions (e.g., hybridizationconditions) will not affect subsequent analyses.

Examples of distinguishable labels for use when hybridizing a pluralityof target nucleic acids to one array are well known in the art andinclude: two or more different emission wavelength fluorescent dyes,like Cy3 and Cy5, combination of fluorescent proteins and dyes, likephycoerythrin and Cy5, two or more isotopes with different energy ofemission, like ³²P and ³³P, gold or silver particles with differentscattering spectra, labels which generate signals under differenttreatment conditions, like temperature, pH, treatment by additionalchemical agents, etc., or generate signals at different time pointsafter treatment. Using one or more enzymes for signal generation allowsfor the use of an even greater variety of distinguishable labels, basedon different substrate specificity of enzymes (alkalinephosphatase/peroxidase).

Further, it is preferable in order to reduce experimental error toreverse the fluorescent labels in two-color differential hybridizationexperiments to reduce biases peculiar to individual genes or array spotlocations. In other words, it is preferable to first measure geneexpression with one labeling (e.g., labeling nucleic acid from a firstcell with a first fluorochrome and nucleic acid from a second cell witha second fluorochrome) of the mRNA from the two cells being measured,and then to measure gene expression from the two cells with reversedlabeling (e.g., labeling nucleic acid from the first cell with thesecond fluorochrome and nucleic acid from the second cell with the firstfluorochrome). Multiple measurements over exposure levels andperturbation control parameter levels provide additional experimentalerror control.

The quality of labeled nucleic acids can be evaluated prior tohybridization to an array. For example, a sample of the labeled nucleicacids can be hybridized to probes derived from the 5′, middle and 3′portions of genes known to be or suspected to be present in the nucleicacid sample. This will be indicative as to whether the labeled nucleicacids are full length nucleic acids or whether they are degraded. In oneembodiment, the GeneChip® Test3 Array from Affymetrix (Santa Clara,Calif.) can be used for that purpose. This array contains probesrepresenting a subset of characterized genes from several organismsincluding mammals. Thus, the quality of a labeled nucleic acid samplecan be determined by hybridization of a fraction of the sample to anarray, such as the GeneChip® Test3 Array from Affymetrix (Santa Clara,Calif.).

(iii) Exemplary Arrays

Preferred arrays, e.g., microarrays, for use according to the inventioninclude one or more probes of genes which are up- or down-regulatedduring bone or cartilage formation, such as one or more genes listed inany of Tables 1, 2, 5, 6 and/or 7. The array may comprise probescorresponding to at least 10, preferably at least 20, at least 50, atleast 100 or at least 1000 genes. The array may comprise probescorresponding to about 10%, 20%, 50%, 70%, 90% or 95% of the geneslisted in any of Tables 1, 2, 5, 6 and/or 7. The array may compriseprobes corresponding to about 10%, 20%, 50%, 70%, 90% or 95% of thegenes listed in any of Tables 1, 2, 5, 6 and/or 7 whose expressionincreases or decreases at least about 2 fold, preferably at least about3 fold, more preferably at least about 4 fold, 5 fold, 7 fold and mostpreferably at least about 10 fold during bone or cartilage formation.One array that can be used is the array used and described in theExamples.

There can be one or more than one probe corresponding to each gene on amicroarray. For example, a microarray may contain from 2 to 20 probescorresponding to one gene and preferably about 5 to 10. The probes maycorrespond to the full length RNA sequence or complement thereof ofgenes that are up- or down-regulated during bone or cartilage formation,or they may correspond to a portion thereof, which portion is ofsufficient length for permitting specific hybridization. Such probes maycomprise from about 50 nucleotides to about 100, 200, 500, or 1000nucleotides or more than 1000 nucleotides. As further described herein,microarrays may contain oligonucleotide probes, consisting of about 10to 50 nucleotides, preferably about 15 to 30 nucleotides and even morepreferably 20-25 nucleotides. The probes are preferably single stranded.The probe will have sufficient complementarity to its target to providefor the desired level of sequence specific hybridization (see below).

Typically, the arrays used in the present invention will have a sitedensity of greater than 100 different probes per cm². Preferably, thearrays will have a site density of greater than 500/cm², more preferablygreater than about 1000/cm², and most preferably, greater than about10,000/cm². Preferably, the arrays will have more than 100 differentprobes on a single substrate, more preferably greater than about 1000different probes still more preferably, greater than about 10,000different probes and most preferably, greater than 100,000 differentprobes on a single substrate.

Microarrays can be prepared by methods known in the art, as describedbelow, or they can be custom made by companies, e.g., Affymetrix (SantaClara, Calif.).

Generally, two types of microarrays can be used. These two types arereferred to as “synthesis” and “delivery.” In the synthesis type, amicroarray is prepared in a step-wise fashion by the in situ synthesisof nucleic acids from nucleotides. With each round of synthesis,nucleotides are added to growing chains until the desired length isachieved. In the delivery type of microarray, preprepared nucleic acidsare deposited onto known locations using a variety of deliverytechnologies. Numerous articles describe the different microarraytechnologies, e.g., Shena et al. (1998) Tibtech 16: 301; Duggan et al.(1999) Nat. Genet. 21:10; Bowtell et al. (1999) Nat. Genet. 21: 25.

One novel synthesis technology is that developed by Affymetrix (SantaClara, Calif.), which combines photolithography technology with DNAsynthetic chemistry to enable high density oligonucleotide microarraymanufacture. Such chips contain up to 400,000 groups of oligonucleotidesin an area of about 1.6 cm². Oligonucleotides are anchored at the 3′ endthereby maximizing the availability of single-stranded nucleic acid forhybridization. Generally such chips, referred to as “GeneChips®” containseveral oligonucleotides of a particular gene, e.g., between 15-20, suchas 16 oligonucleotides. Since Affymetrix (Santa Clara, Calif.) sellscustom made microarrays, microarrays containing genes which are up- ordown-regulated during bone formation can be ordered for purchase fromAffymetrix (Santa Clara, Calif.).

Microarrays can also be prepared by mechanical microspotting, e.g.,those commercialized at Synteni (Fremont, Calif.). According to thesemethods, small quantities of nucleic acids are printed onto solidsurfaces. Microspotted arrays prepared at Synteni contain as many as10,000 groups of cDNA in an area of about 3.6 cm².

A third group of microarray technologies consist in the “drop-on-demand”delivery approaches, the most advanced of which are the ink-jettingtechnologies, which utilize piezoelectric and other forms of propulsionto transfer nucleic acids from miniature nozzles to solid surfaces.Inkjet technologies is developed at several centers including IncytePharmaceuticals (Palo Alto, Calif.) and Protogene (Palo Alto, Calif.).This technology results in a density of 10,000 spots per cm². See also,Hughes et al. (2001) Nat. Biotechn. 19:342.

Arrays preferably include control and reference nucleic acids. Controlnucleic acids are nucleic acids which serve to indicate that thehybridization was effective. For example, all Affymetrix (Santa Clara,Calif.) expression arrays contain sets of probes for several prokaryoticgenes, e.g., bioB, bioC and bioD from biotin synthesis of E. coli andcre from P1 bacteriophage. Hybridization to these arrays is conducted inthe presence of a mixture of these genes or portions thereof, such asthe mix provided by Affymetrix (Santa Clara, Calif.) to that effect(Part Number 900299), to thereby confirm that the hybridization waseffective. Control nucleic acids included with the target nucleic acidscan also be mRNA synthesized from cDNA clones by in vitro transcription.Other control genes that may be included in arrays are polyA controls,such as dap, lys, phe, thr, and trp (which are included on AffymetrixGeneChips®)

Reference nucleic acids allow the normalization of results from oneexperiment to another, and to compare multiple experiments on aquantitative level. Exemplary reference nucleic acids includehousekeeping genes of known expression levels, e.g., GAPDH, hexokinaseand actin.

Mismatch controls may also be provided for the probes to the targetgenes, for expression level controls or for normalization controls.Mismatch controls are oligonucleotide probes or other nucleic acidprobes identical to their corresponding test or control probes exceptfor the presence of one or more mismatched bases.

Arrays may also contain probes that hybridize to more than one allele ofa gene. For example the array can contain one probe that recognizesallele 1 and another probe that recognizes allele 2 of a particulargene.

Microarrays can be prepared as follows. In one embodiment, an array ofoligonucleotides is synthesized on a solid support. Exemplary solidsupports include glass, plastics, polymers, metals, metalloids,ceramics, organics, etc. Using chip masking technologies andphotoprotective chemistry it is possible to generate ordered arrays ofnucleic acid probes. These arrays, which are known, e.g., as “DNAchips,” or as very large scale immobilized polymer arrays (“VLSIPS™”arrays) can include millions of defined probe regions on a substratehaving an area of about 1 cm² to several cm², thereby incorporating setsof from a few to millions of probes (see, e.g., U.S. Pat. No.5,631,734).

The construction of solid phase nucleic acid arrays to detect targetnucleic acids is well described in the literature. See, Fodor et al.(1991) Science, 251: 767-777; Sheldon et al. (1993) Clinical Chemistry39(4): 718-719; Kozal et al. (1996) Nature Medicine 2(7): 753-759 andHubbell U.S. Pat. No. 5,571,639; Pinkel et al. PCT/US95/16155 (WO96/17958); U.S. Pat. Nos. 5,677,195; 5,624,711; 5,599,695; 5,451,683;5,424,186; 5,412,087; 5,384,261; 5,252,743 and 5,143,854; PCT PatentPublication Nos. 92/10092 and 93/09668; and PCT WO 97/10365. In brief, acombinatorial strategy allows for the synthesis of arrays containing alarge number of probes using a minimal number of synthetic steps. Forinstance, it is possible to synthesize and attach all possible DNA 8 meroligonucleotides (48, or 65,536 possible combinations) using only 32chemical synthetic steps. In general, VLSIPS™ procedures provide amethod of producing 4n different oligonucleotide probes on an arrayusing only 4n synthetic steps (see, e.g., U.S. Pat. No. 5,631,7345,143,854 and PCT Patent Publication Nos. WO 90/15070; WO 95/11995 andWO 92/10092).

Light-directed combinatorial synthesis of oligonucleotide arrays on aglass surface can be performed with automated phosphoramidite chemistryand chip masking techniques similar to photoresist technologies in thecomputer chip industry. Typically, a glass surface is derivatized with asilane reagent containing a functional group, e.g., a hydroxyl or aminegroup blocked by a photolabile protecting group. Photolysis through aphotolithographic mask is used selectively to expose functional groupswhich are then ready to react with incoming 5′-photoprotected nucleosidephosphoramidites. The phosphoramidites react only with those sites whichare illuminated (and thus exposed by removal of the photolabile blockinggroup). Thus, the phosphoramidites only add to those areas selectivelyexposed from the preceding step. These steps are repeated until thedesired array of sequences have been synthesized on the solid surface.

Algorithms for design of masks to reduce the number of synthesis cyclesare described by Hubbel et al., U.S. Pat. No. 5,571,639 and U.S. Pat.No. 5,593,839. A computer system may be used to select nucleic acidprobes on the substrate and design the layout of the array as describedin U.S. Pat. No. 5,571,639.

Another method for synthesizing high density arrays is described in U.S.Pat. No. 6,083,697. This method utilizes a novel chemical amplificationprocess using a catalyst system which is initiated by radiation toassist in the synthesis the polymer sequences. Such methods include theuse of photosensitive compounds which act as catalysts to chemicallyalter the synthesis intermediates in a manner to promote formation ofpolymer sequences. Such photosensitive compounds include what aregenerally referred to as radiation-activated catalysts (RACs), and morespecifically photo activated catalysts (PACs). The RACs can bythemselves chemically alter the synthesis intermediate or they canactivate an autocatalytic compound which chemically alters the synthesisintermediate in a manner to allow the synthesis intermediate tochemically combine with a later added synthesis intermediate or othercompound.

Arrays can also be synthesized in a combinatorial fashion by deliveringmonomers to cells of a support by mechanically constrained flowpaths.See Winkler et al., EP 624,059. Arrays can also be synthesized byspotting monomers reagents on to a support using an ink jet printer. Seeid. and Pease et al., EP 728,520.

cDNA probes can be prepared according to methods known in the art andfurther described herein, e.g., reverse-transcription PCR (RT-PCR) ofRNA using sequence specific primers. Oligonucleotide probes can besynthesized chemically. Sequences of the genes or cDNA from which probesare made can be obtained, e.g., from GenBank, other public databases orpublications.

Nucleic acid probes can be natural nucleic acids, chemically modifiednucleic acids, e.g., composed of nucleotide analogs, as long as theyhave activated hydroxyl groups compatible with the linking chemistry.The protective groups can, themselves, be photolabile. Alternatively,the protective groups can be labile under certain chemical conditions,e.g., acid. In this example, the surface of the solid support cancontain a composition that generates acids upon exposure to light. Thus,exposure of a region of the substrate to light generates acids in thatregion that remove the protective groups in the exposed region. Also,the synthesis method can use 3′-protected 5′-0-phosphoramidite-activateddeoxynucleoside. In this case, the oligonucleotide is synthesized in the5′ to 3′ direction, which results in a free 5′ end.

Oligonucleotides of an array can be synthesized using a 96 wellautomated multiplex oligonucleotide synthesizer (A.M.O.S.) that iscapable of making thousands of oligonucleotides (Lashkari et al. (1995)PNAS 93: 7912) can be used.

It will be appreciated that oligonucleotide design is influenced by theintended application. For example, it may be desirable to have similarmelting temperatures for all of the probes. Accordingly, the length ofthe probes are adjusted so that the melting temperatures for all of theprobes on the array are closely similar (it will be appreciated thatdifferent lengths for different probes may be needed to achieve aparticular T[m] where different probes have different GC contents).Although melting temperature is a primary consideration in probe design,other factors are optionally used to further adjust probe construction,such as selecting against primer self-complementarity and the like.

Arrays, e.g., microarrays, may conveniently be stored followingfabrication or purchase for use at a later time. Under appropriateconditions, the subject arrays are capable of being stored for at leastabout 6 months and may be stored for up to one year or longer. Arraysare generally stored at temperatures between about −20° C. to roomtemperature, where the arrays are preferably sealed in a plasticcontainer, e.g. bag, and shielded from light.

(iv) Hybridization of the Target Nucleic Acids to the Microarray

The next step is to contact the target nucleic acids with the arrayunder conditions sufficient for binding between the target nucleic acidsand the probes of the array. In a preferred embodiment, the targetnucleic acids will be contacted with the array under conditionssufficient for hybridization to occur between the target nucleic acidsand probes on the microarray, where the hybridization conditions will beselected in order to provide for the desired level of hybridizationspecificity.

Contact of the array and target nucleic acids involves contacting thearray with an aqueous medium comprising the target nucleic acids.Contact may be achieved in a variety of different ways depending onspecific configuration of the array. For example, where the array simplycomprises the pattern of size separated probes on the surface of a“plate-like” rigid substrate, contact may be accomplished by simplyplacing the array in a container comprising the target nucleic acidsolution, such as a polyethylene bag, and the like. In other embodimentswhere the array is entrapped in a separation media bounded by two rigidplates, the opportunity exists to deliver the target nucleic acids viaelectrophoretic means. Alternatively, where the array is incorporatedinto a biochip device having fluid entry and exit ports, the targetnucleic acid solution can be introduced into the chamber in which thepattern of target molecules is presented through the entry port, wherefluid introduction could be performed manually or with an automateddevice. In multiwell embodiments, the target nucleic acid solution willbe introduced in the reaction chamber comprising the array, eithermanually, e.g. with a pipette, or with an automated fluid handlingdevice.

Contact of the target nucleic acid solution and the probes will bemaintained for a sufficient period of time for binding between thetarget and the probe to occur. Although dependent on the nature of theprobe and target, contact will generally be maintained for a period oftime ranging from about 10 min to 24 hrs, usually from about 30 min to12 hrs and more usually from about 1 hr to 6 hrs.

When using commercially available microarrays, adequate hybridizationconditions are provided by the manufacturer. When using non-commercialmicroarrays, adequate hybridization conditions can be determined basedon the following hybridization guidelines, as well as on thehybridization conditions described in the numerous published articles onthe use of microarrays.

Nucleic acid hybridization and wash conditions are optimally chosen sothat the probe “specifically binds” or “specifically hybridizes” to aspecific array site, i.e., the probe hybridizes, duplexes or binds to asequence array site with a complementary nucleic acid sequence but doesnot hybridize to a site with a non-complementary nucleic acid sequence.As used herein, one polynucleotide sequence is considered complementaryto another when, if the shorter of the polynucleotides is less than orequal to 25 bases, there are no mismatches using standard base-pairingrules or, if the shorter of the polynucleotides is longer than 25 bases,there is no more than a 5% mismatch. Preferably, the polynucleotides areperfectly complementary (no mismatches). It can easily be demonstratedthat specific hybridization conditions result in specific hybridizationby carrying out a hybridization assay including negative controls.

Hybridization is carried out in conditions permitting essentiallyspecific hybridization. The length of the probe and GC content willdetermine the Tm of the hybrid, and thus the hybridization conditionsnecessary for obtaining specific hybridization of the probe to thetemplate nucleic acid. These factors are well known to a person of skillin the art, and can also be tested in assays. An extensive guide to thehybridization of nucleic acids is found in Tijssen (1993), “LaboratoryTechniques in biochemistry and molecular biology-hybridization withnucleic acid probes.” Generally, stringent conditions are selected to beabout 5° C. lower than the thermal melting point (Tm) for the specificsequence at a defined ionic strength and pH. The Tm is the temperature(under defined ionic strength and pH) at which 50% of the targetsequence hybridizes to a perfectly matched probe. Highly stringentconditions are selected to be equal to the Tm point for a particularprobe. Sometimes the term “Td” is used to define the temperature atwhich at least half of the probe dissociates from a perfectly matchedtarget nucleic acid. In any case, a variety of estimation techniques forestimating the Tm or Td are available, and generally described inTijssen, supra. Typically, G-C base pairs in a duplex are estimated tocontribute about 3° C. to the Tm, while A-T base pairs are estimated tocontribute about 2° C., up to a theoretical maximum of about 80-100° C.However, more sophisticated models of Tm and Td are available andappropriate in which G-C stacking interactions, solvent effects, thedesired assay temperature and the like are taken into account. Forexample, probes can be designed to have a dissociation temperature (Td)of approximately 60° C., using the formula:Td=(((((3×#GC)+(2×#AT))×37)−562)/#bp)−5; where #GC, #AT, and #bp are thenumber of guanine-cytosine base pairs, the number of adenine-thyminebase pairs, and the number of total base pairs, respectively, involvedin the annealing of the probe to the template DNA.

The stability difference between a perfectly matched duplex and amismatched duplex, particularly if the mismatch is only a single base,can be quite small, corresponding to a difference in Tm between the twoof as little as 0.5 degrees. See Tibanyenda, N. et al., Eur. J. Biochem.139:19 (1984) and Ebel, S. et al., Biochem. 31:12083 (1992). Moreimportantly, it is understood that as the length of the homology regionincreases, the effect of a single base mismatch on overall duplexstability decreases.

Theory and practice of nucleic acid hybridization is described, e.g., inS. Agrawal (ed.) Methods in Molecular Biology, volume 20; and Tijssen(1993) Laboratory Techniques in biochemistry and molecularbiology-hybridization with nucleic acid probes, e.g., part I chapter 2“Overview of principles of hybridization and the strategy of nucleicacid probe assays”, Elsevier, N.Y. provide a basic guide to nucleic acidhybridization.

Certain microarrays are of “active” nature, i.e., they provideindependent electronic control over all aspects of the hybridizationreaction (or any other affinity reaction) occurring at each specificmicrolocation. These devices provide a new mechanism for affectinghybridization reactions which is called electronic stringency control(ESC). Such active devices can electronically produce “differentstringency conditions” at each microlocation. Thus, all hybridizationscan be carried out optimally in the same bulk solution. These arrays aredescribed in U.S. Pat. No. 6,051,380 by Sosnowski et al.

In a preferred embodiment, background signal is reduced by the use of adetergent (e.g., C-TAB) or a blocking reagent (e.g., sperm DNA,cot-1DNA, etc.) during the hybridization to reduce non-specific binding.In a particularly preferred (embodiment, the hybridization is performedin the presence of about 0.5 mg/ml DNA (e.g., herring sperm DNA). Theuse of blocking agents in hybridization is well known to those of skillin the art (see, e.g., Chapter 8 in Laboratory Techniques inBiochemistry and Molecular Biology, Vol. 24: Hybridization With NucleicAcid Probes, P. Tijssen, ed. Elsevier, N.Y., (1993)).

The method may or may not further comprise a non-bound label removalstep prior to the detection step, depending on the particular labelemployed on the target nucleic acid. For example, in certain assayformats (e.g., “homogenous assay formats”) a detectable signal is onlygenerated upon specific binding of target to probe. As such, in theseassay formats, the hybridization pattern may be detected without anon-bound label removal step. In other embodiments, the label employedwill generate a signal whether or not the target is specifically boundto its probe. In such embodiments, the non-bound labeled target isremoved from the support surface. One means of removing the non-boundlabeled target is to perform the well known technique of washing, wherea variety of wash solutions and protocols for their use in removingnon-bound label are known to those of skill in the art and may be used.Alternatively, non-bound labeled target can be removed byelectrophoretic means.

Where all of the target sequences are detected using the same label,different arrays will be employed for each physiological source or timepoint (where different could include using the same array at differenttimes). The above methods can be varied to provide for multiplexanalysis, by employing different and distinguishable labels for thedifferent target populations (representing each of the differentphysiological sources or time points being assayed). According to thismultiplex method, the same array is used at the same time for each ofthe different target populations.

In another embodiment, hybridization is monitored in real time using acharge-coupled device (CCD) imaging camera (Guschin et al. (1997) Anal.Biochem. 250:203). Synthesis of arrays on optical fibre bundles allowseasy and sensitive reading (Healy et al. (1997) Anal. Biochem. 251:270).In another embodiment, real time hybridization detection is carried outon microarrays without washing using evanescent wave effect that excitesonly fluorophores that are bound to the surface (see, e.g., Stimpson etal. (1995) PNAS 92:6379).

(v) Detection of Hybridization and Analysis of Results

The above steps result in the production of hybridization patterns oftarget nucleic acid on the array surface. These patterns may bevisualized or detected in a variety of ways, with the particular mannerof detection being chosen based on the particular label of the targetnucleic acid. Representative detection means include scintillationcounting, autoradiography, fluorescence measurement, colorimetricmeasurement, light emission measurement, light scattering, and the like.

One method of detection includes an array scanner that is commerciallyavailable from Affymetrix (Santa Clara, Calif.), e.g., the 417™ Arrayer,the 418™ Array Scanner, or the Agilent GeneArray™ Scanner. This scanneris controlled from the system computer with a Windows® interface andeasy-to-use software tools. The output is a 16-bit.tif file that can bedirectly imported into or directly read by a variety of softwareapplications. Preferred scanning devices are described in, e.g., U.S.Pat. Nos. 5,143,854 and 5,424,186.

When fluorescently labeled probes are used, the fluorescence emissionsat each site of a transcript array can be detected by scanning confocallaser microscopy. In one embodiment, a separate scan, using theappropriate excitation line, is carried out for each of the twofluorophores used. Alternatively, a laser can be used that allowssimultaneous specimen illumination at wavelengths specific to the twofluorophores and emissions from the two fluorophores can be analyzedsimultaneously (see Shalon et al., 1996, A DNA microarray system foranalyzing complex DNA samples using two-color fluorescent probehybridization, Genome Research 6:639-645). In a preferred embodiment,the arrays are scanned with a laser fluorescent scanner with a computercontrolled X-Y stage and a microscope objective. Sequential excitationof the two fluorophores can be achieved with a multi-line, mixed gaslaser and the emitted light is split by wavelength and detected with twophotomultiplier tubes. In one embodiment in which fluorescent targetnucleic acids are used, the arrays may be scanned using lasers to excitefluorescently labeled targets that have hybridized to regions of probearrays, which can then be imaged using charged coupled devices (“CCDs”)for a wide field scanning of the array. Fluorescence laser scanningdevices are described, e.g., in Schena et al., 1996, Genome Res.6:639-645. Alternatively, the fiber-optic bundle described by Fergusonet al., 1996, Nature Biotech. 14:1681-1684, may be used to monitor mRNAabundance levels.

Following the data gathering operation, the data will typically bereported to a data analysis operation. To facilitate the sample analysisoperation, the data obtained by the reader from the device willtypically be analyzed using a digital computer. Typically, the computerwill be appropriately programmed for receipt and storage of the datafrom the device, as well as for analysis and reporting of the datagathered, e.g., subtraction of the background, deconvolution multi-colorimages, flagging or removing artifacts, verifying that controls haveperformed properly, normalizing the signals, interpreting fluorescencedata to determine the amount of hybridized target, normalization ofbackground and single base mismatch hybridizations, and the like. In apreferred embodiment, a system comprises a search function that allowsone to search for specific patterns, e.g., patterns relating todifferential gene expression of genes which are up- or down-regulatedduring bone or cartilage formation. A system preferably allows one tosearch for patterns of gene expression between more than two samples.

A desirable system for analyzing data is a general and flexible systemfor the visualization, manipulation, and analysis of gene expressiondata. Such a system preferably includes a graphical user interface forbrowsing and navigating through the expression data, allowing a user toselectively view and highlight the genes of interest. The system alsopreferably includes sort and search functions and is preferablyavailable for general users with PC, Mac or Unix workstations. Alsopreferably included in the system are clustering algorithms that arequalitatively more efficient than existing ones. The accuracy of suchalgorithms is preferably hierarchically adjustable so that the level ofdetail of clustering can be systematically refined as desired.

Various algorithms are available for analyzing the gene expressionprofile data, e.g., the type of comparisons to perform. In certainembodiments, it is desirable to group genes that are co-regulated. Thisallows the comparison of large numbers of profiles. A preferredembodiment for identifying such groups of genes involves clusteringalgorithms (for reviews of clustering algorithms, see, e.g., Fukunaga,1990, Statistical Pattern Recognition, 2nd Ed., Academic Press, SanDiego; Everitt, 1974, Cluster Analysis, London: Heinemann Educ. Books;Hartigan, 1975, Clustering Algorithms, New York: Wiley; Sneath andSokal, 1973, Numerical Taxonomy, Freeman; Anderberg, 1973, ClusterAnalysis for Applications, Academic Press: New York).

Clustering analysis is useful in helping to reduce complex patterns ofthousands of time curves into a smaller set of representative clusters.Some systems allow the clustering and viewing of genes based onsequences. Other systems allow clustering based on other characteristicsof the genes, e.g., their level of expression (see, e.g., U.S. Pat. No.6,203,987). Other systems permit clustering of time curves (see, e.g.U.S. Pat. No. 6,263,287). Cluster analysis can be performed using thehclust routine (see, e.g., “hclust” routine from the software packageS-Plus, MathSoft, Inc., Cambridge, Mass.).

In some specific embodiments, genes are grouped according to the degreeof co-variation of their transcription, presumably co-regulation, asdescribed in U.S. Pat. No. 6,203,987. Groups of genes that haveco-varying transcripts are termed “genesets.” Cluster analysis or otherstatistical classification methods can be used to analyze theco-variation of transcription of genes in response to a variety ofperturbations, e.g. caused by a disease or a drug. In one specificembodiment, clustering algorithms are applied to expression profiles toconstruct a “similarity tree” or “clustering tree” which relates genesby the amount of co-regulation exhibited. Genesets are defined on thebranches of a clustering tree by cutting across the clustering tree atdifferent levels in the branching hierarchy.

In some embodiments, a gene expression profile is converted to aprojected gene expression profile. The projected gene expression profileis a collection of geneset expression values. The conversion isachieved, in some embodiments, by averaging the level of expression ofthe genes within each geneset. In some other embodiments, other linearprojection processes may be used. The projection operation expresses theprofile on a smaller and biologically more meaningful set ofcoordinates, reducing the effects of measurement errors by averagingthem over each cellular constituent sets and aiding biologicalinterpretation of the profile.

Values that can be compared include gross expression levels; averages ofexpression levels, e.g., from different experiments, different samplesfrom the same subject or samples from different subjects; and ratios ofexpression levels, e.g., between patients and normal controls.

A variety of other statistical methods are available to assess thedegree of relatedness in expression patterns of different genes. Certainstatistical methods may be broken into two related portions: metrics fordetermining the relatedness of the expression pattern of one or moregene, and clustering methods, for organizing and classifying expressiondata based on a suitable metric (Sherlock, 2000, Curr. Opin. Immunol.12:201-205; Butte et al., 2000, Pacific Symposium on Biocomputing,Hawaii, World Scientific, p. 418-29).

In one embodiment, Pearson correlation may be used as a metric. Inbrief, for a given gene, each data point of gene expression leveldefines a vector describing the deviation of the gene expression fromthe overall mean of gene expression level for that gene across allconditions. Each gene's expression pattern can then be viewed as aseries of positive and negative vectors. A Pearson correlationcoefficient can then be calculated by comparing the vectors of each geneto each other. An example of such a method is described in Eisen et al.(1998, supra). Pearson correlation coefficients account for thedirection of the vectors, but not the magnitudes.

In another embodiment, Euclidean distance measurements may be used as ametric. In these methods, vectors are calculated for each gene in eachcondition and compared on the basis of the absolute distance inmultidimensional space between the points described by the vectors forthe gene.

In a further embodiment, the relatedness of gene expression patterns maybe determined by entropic calculations (Butte et al. 2000, supra).Entropy is calculated for each gene's expression pattern. The calculatedentropy for two genes is then compared to determine the mutualinformation. Mutual information is calculated by subtracting the entropyof the joint gene expression patterns from the entropy for calculatedfor each gene individually. The more different two gene expressionpatterns are, the higher the joint entropy will be and the lower thecalculated mutual information. Therefore, high mutual informationindicates a non-random relatedness between the two expression patterns.

The different metrics for relatedness may be used in various ways toidentify clusters of genes. In one embodiment, comprehensive pairwisecomparisons of entropic measurements will identify clusters of geneswith particularly high mutual information. In preferred embodiments,expression patterns for two genes are correlated if the normalizedmutual information score is greater than or equal to 0.7, and preferablygreater than 0.8, greater than 0.9 or greater than 0.95. In alternativeembodiments, a statistical significance for mutual information may beobtained by randomly permuting the expression measurements 30 times anddetermining the highest mutual information measurement obtained fromsuch random associations. All clusters with a mutual information higherthan can be obtained randomly after 30 permutations are statisticallysignificant. In a further embodiment, expression patterns for two genesare correlated if the correlation coefficient is greater than or equalto 0.8, and preferably greater than 0.85, 0.9 or, most preferablygreater than 0.95.

In another embodiment, agglomerative clustering methods may be used toidentify gene clusters. In one embodiment, Pearson correlationcoefficients or Euclidean metrics are determined for each gene and thenused as a basis for forming a dendrogram. In one example, genes werescanned for pairs of genes with the closest correlation coefficient.These genes are then placed on two branches of a dendrogram connected bya node, with the distance between the depth of the branches proportionalto the degree of correlation. This process continues, progressivelyadding branches to the tree. Ultimately a tree is formed in which genesconnected by short branches represent clusters, while genes connected bylonger branches represent genes that are not clustered together. Thepoints in multidimensional space by Euclidean metrics may also be usedto generate dendrograms.

In yet another embodiment, divisive clustering methods may be used. Forexample, vectors are assigned to each gene's expression pattern, and tworandom vectors are generated. Each gene is then assigned to one of thetwo random vectors on the basis of probability of matching that vector.The random vectors are iteratively recalculated to generate twocentroids that split the genes into two groups. This split forms themajor branch at the bottom of a dendrogram. Each group is then furthersplit in the same manner, ultimately yielding a fully brancheddendrogram.

In a further embodiment, self-organizing maps (SOM) may be used togenerate clusters. In general, the gene expression patterns are plottedin n-dimensional space, using a metric such as the Euclidean metricsdescribed above. A grid of centroids is then placed onto then-dimensional space and the centroids are allowed to migrate towardsclusters of points, representing clusters of gene expression. Finallythe centroids represent a gene expression pattern that is a sort ofaverage of a gene cluster. In certain embodiments, SOM may be used togenerate centroids, and the genes clustered at each centroid may befurther represented by a dendrogram. An exemplary method is described inTamayo et al., 1999, PNAS 96:2907-12. Once centroids are formed,correlation must be evaluated by one of the methods described supra.

2.2. Other Methods for Determining Gene Expression Levels

In certain embodiments, it is sufficient to determine the expression ofone or only a few genes, as opposed to hundreds or thousands of genes.Although microarrays can be used in these embodiments, various othermethods of detection of gene expression are available. This sectiondescribes a few exemplary methods for detecting and quantifying mRNA orpolypeptide encoded thereby. Where the first step of the methodsincludes isolation of mRNA from cells, this step can be conducted asdescribed above. Labeling of one or more nucleic acids can be performedas described above.

In one embodiment, mRNA obtained form a sample is reverse transcribedinto a first cDNA strand and subjected to PCR, e.g., RT-PCR. Housekeeping genes, or other genes whose expression does not vary can be usedas internal controls and controls across experiments. Following the PCRreaction, the amplified products can be separated by electrophoresis anddetected. By using quantitative PCR, the level of amplified product willcorrelate with the level of RNA that was present in the sample. Theamplified samples can also be separated on a agarose or polyacrylamidegel, transferred onto a filter, and the filter hybridized with a probespecific for the gene of interest. Numerous samples can be analyzedsimultaneously by conducting parallel PCR amplification, e.g., bymultiplex PCR.

A quantitative PCR technique that can be used is based on the use ofTaqMan™ probes. Specific sequence detection occurs by amplification oftarget sequences in the PE Applied Biosystems 7700 Sequence DetectionSystem in the presence of an oligonucleotide probe labeled at the 5′ and3′ ends with a reporter and quencher fluorescent dye, respectively (FQprobe), which anneals between the two PCR primers. Only specific productwill be detected when the probe is bound between the primers. As PCRamplification proceeds, the 5′-nuclease activity of Taq polymeraseinitially cleaves the reporter dye from the probe. The signal generatedwhen the reporter dye is physically separated from the quencher dye isdetected by measuring the signal with an attached CCD camera. Eachsignal generated equals one probe cleaved which corresponds toamplification of one target strand. PCR reactions may be set up usingthe PE Applied Biosystem TaqMan PCR Core Reagent Kit according to theinstructions supplied. This technique is further described, e.g., inU.S. Pat. No. 6,326,462.

In another embodiment, mRNA levels is determined by dotblot analysis andrelated methods (see, e.g., G. A. Beltz et al., in Methods inEnzymology, Vol. 100, Part B, R. Wu, L. Grossmam, K. Moldave, Eds.,Academic Press, New York, Chapter 19, pp. 266-308, 1985). In oneembodiment, a specified amount of RNA extracted from cells is blotted(i.e., non-covalently bound) onto a filter, and the filter is hybridizedwith a probe of the gene of interest. Numerous RNA samples can beanalyzed simultaneously, since a blot can comprise multiple spots ofRNA. Hybridization is detected using a method that depends on the typeof label of the probe. In another dotblot method, one or more probes ofone or more genes which are up- or down-regulated during bone orcartilage formation are attached to a membrane, and the membrane isincubated with labeled nucleic acids obtained from and optionallyderived from RNA of a cell or tissue of a subject. Such a dotblot isessentially an array comprising fewer probes than a microarray.

“Dot blot” hybridization gained wide-spread use, and many versions weredeveloped (see, e.g., M. L. M. Anderson and B. D. Young, in Nucleic AcidHybridization—A Practical Approach, B. D. Hames and S. J. Higgins, Eds.,IRL Press, Washington D.C., Chapter 4, pp. 73-111, 1985).

Another format, the so-called “sandwich” hybridization, involvescovalently attaching oligonucleotide probes to a solid support and usingthem to capture and detect multiple nucleic acid targets (see, e.g., M.Ranki et al., Gene, 21, pp. 77-85, 1983; A. M. Palva, T. M. Ranki, andH. E. Soderlund, in UK Patent Application GB 2156074A, Oct. 2, 1985; T.M. Ranki and H. E. Soderlund in U.S. Pat. No. 4,563,419, Jan. 7, 1986;A. D. B. Malcolm and J. A. Langdale, in PCT WO 86/03782, Jul. 3, 1986;Y. Stabinsky, in U.S. Pat. No. 4,751,177, Jan. 14, 1988; T. H. Adams etal., in PCT WO 90/01564, Feb. 22, 1990; R. B. Wallace et al. 6 NucleicAcid Res. 11, p. 3543, 1979; and B. J. Connor et al., 80 Proc. Natl.Acad. Sci. USA pp. 278-282, 1983). Multiplex versions of these formatsare called “reverse dot blots.”

mRNA levels can also be determined by Northern blots. Specific amountsof RNA are separated by gel electrophoresis and transferred onto afilter which is then hybridized with a probe corresponding to the geneof interest. This method, although more burdensome when numerous samplesand genes are to be analyzed provides the advantage of being veryaccurate.

A preferred method for high throughput analysis of gene expression isthe serial analysis of gene expression (SAGE) technique, first describedin Velculescu et al. (1995) Science 270, 484-487. Among the advantagesof SAGE is that it has the potential to provide detection of all genesexpressed in a given cell type, provides quantitative information aboutthe relative expression of such genes, permits ready comparison of geneexpression of genes in two cells, and yields sequence information thatcan be used to identify the detected genes. Thus far, SAGE methodologyhas proved itself to reliably detect expression of regulated andnonregulated genes in a variety of cell types (Velculescu et al. (1997)Cell 88, 243-251; Zhang et al. (1997) Science 276, 1268-1272 andVelculescu et al. (1999) Nat. Genet. 23, 387-388).

Techniques for producing and probing nucleic acids are furtherdescribed, for example, in Sambrook et al., “Molecular Cloning: ALaboratory Manual” (New York, Cold Spring Harbor Laboratory, 1989).

Alternatively, the level of expression of one or more genes which areup- or down-regulated during bone or cartilage formation is determinedby in situ hybridization. In one embodiment, a tissue sample is obtainedfrom a subject, the tissue sample is sliced, and in situ hybridizationis performed according to methods known in the art, to determine thelevel of expression of the genes of interest.

In other methods, the level of expression of a gene is detected bymeasuring the level of protein encoded by the gene. This can be done,e.g., by immunoprecipitation, ELISA, or immunohistochemistry using anagent, e.g., an antibody, that specifically detects the protein encodedby the gene. Other techniques include Western blot analysis.Immunoassays are commonly used to quantitate the levels of proteins incell samples, and many other immunoassay techniques are known in theart. The invention is not limited to a particular assay procedure, andtherefore is intended to include both homogeneous and heterogeneousprocedures. Exemplary immunoassays which can be conducted according tothe invention include fluorescence polarization immunoassay (FPIA),fluorescence immunoassay (FIA), enzyme immunoassay (EIA), nephelometricinhibition immunoassay (NIA), enzyme linked immunosorbent assay (ELISA),and radioimmunoassay (RIA). An indicator moiety, or label group, can beattached to the subject antibodies and is selected so as to meet theneeds of various uses of the method which are often dictated by theavailability of assay equipment and compatible immunoassay procedures.General techniques to be used in performing the various immunoassaysnoted above are known to those of ordinary skill in the art.

In the case of polypeptides which are secreted from cells, the level ofexpression of these polypeptides can be measured in biological fluids.

2.3. Data Analysis Methods

Comparison of the expression levels of one or more genes which are up-or down-regulated in a sample, e.g., of a patient, with referenceexpression levels, e.g., in normal cells undergoing bone or cartilageformation, is preferably conducted using computer systems. In oneembodiment, one or more expression levels are obtained in two cells andthese two sets of expression levels are introduced into a computersystem for comparison. In a preferred embodiment, one set of one or moreexpression levels is entered into a computer system for comparison withvalues that are already present in the computer system, or incomputer-readable form that is then entered into the computer system.

In one embodiment, the invention provides a computer readable form ofthe gene expression profile data of the invention, or of valuescorresponding to the level of expression of at least one gene which isup- or down-regulated during bone or cartilage formation. The values canbe mRNA expression levels obtained from experiments, e.g., microarrayanalysis. The values can also be mRNA levels normalized relative to areference gene whose expression is constant in numerous cells undernumerous conditions, e.g., GAPDH. In other embodiments, the values inthe computer are ratios of, or differences between, normalized ornon-normalized mRNA levels in different samples.

The computer readable medium may comprise values of at least 2, at least3, at least 5, 10, 20, 50, 100, 200, 500 or more genes, e.g., geneslisted in Tables 1, 2, 5, 6 and/or 7. In a preferred embodiment, thecomputer readable medium comprises at least one expression profile.

Gene expression data can be in the form of a table, such as an Exceltable. The data can be alone, or it can be part of a larger database,e.g., comprising other expression profiles, e.g., publicly availabledatabase. The computer readable form can be in a computer. In anotherembodiment, the invention provides a computer displaying the geneexpression profile data.

Although the invention provides methods in which the level of expressionof a single gene can be compared in two or more cells or tissue samples,in a preferred embodiment, the level of expression of a plurality ofgenes is compared. For example, the level of expression of at least 2,at least 3, at least 5, 10, 20, 50, 100, 200, 500 or more genes, e.g.,genes listed in Tables 1, 2, 5, 6 and/or 7 can be compared. In apreferred embodiment, expression profiles are compared.

In one embodiment, the invention provides a method for determining thesimilarity between the level of expression of one or more genes whichare up- or down-regulated during bone or cartilage formation in a firstcell, e.g., a cell of a subject, and that in a second cell. The methodpreferably comprises obtaining the level of expression of one or moregenes which are up- or down-regulated during bone or cartilage formationin a first cell and entering these values into a computer comprising (i)a database including records comprising values corresponding to levelsof expression of one or more genes which are up- or down-regulatedduring bone or cartilage formation in a second cell, and (ii) processorinstructions, e.g., a user interface, capable of receiving a selectionof one or more values for comparison purposes with data that is storedin the computer. The computer may further comprise a means forconverting the comparison data into a diagram or chart or other type ofoutput.

In another embodiment, values representing expression levels of one ormore genes which are up- or down-regulated during bone or cartilageformation are entered into a computer system that comprises one or moredatabases with reference expression levels obtained from more than onecell. For example, the computer may comprise expression data ofdiseased, e.g., bone or cartilage cells of an osteoporosis patient, andnormal cells. The computer may also comprise expression data of genes atdifferent time points during bone or cartilage formation, e.g., the dataset forth in Tables 1, 2, 5, 6 and/or 7. Instructions are provided tothe computer, and the computer is capable of comparing the data enteredwith the data in the computer to determine whether the data entered ismore similar to one or the other gene expression data stored in thecomputer.

In another embodiment, the computer comprises values of expressionlevels in cells of subjects at different stages of a disease relating tobone or cartilage formation or resorption, and the computer is capableof comparing expression data entered into the computer with the datastored, and produce results indicating to which of the expression datain the computer, the one entered is most similar, such as to determinethe stage of the disease in the subject.

In yet another embodiment, the reference expression data in the computerare expression data from cells of one or more subjects having a diseaserelating to bone or cartilage formation or resorption, which cells aretreated in vivo or in vitro with a drug used for therapy of the disease.Upon entering of expression data of a cell of a subject treated in vitroor in vivo with the drug, the computer is instructed to compare the dataentered with the data in the computer, and to provide results indicatingwhether the expression data input into the computer are more similar tothose of a cell of a subject that is responsive to the drug or moresimilar to those of a cell of a subject that is not responsive to thedrug. Thus, the results indicate whether the subject is likely torespond to the treatment with the drug or unlikely to respond to it.

The reference expression data may also be from cells of subjectsresponding or not responding to several different treatments, and thecomputer system indicates a preferred treatment for the subject.Accordingly, the invention provides a method for selecting a therapy fora patient having a disease relating to bone or cartilage formation orresorption, the method comprising: (i) providing the level of expressionof one or more genes which are up- or down-regulated during bone orcartilage formation in a diseased cell of the patient; (ii) providing aplurality of reference expression levels, each associated with atherapy, wherein the subject expression levels and each referenceexpression level has a plurality of values, each value representing thelevel of expression of a gene that is up- or down-regulated during boneor cartilage formation; and (iii) selecting the reference expressionlevels most similar to the subject expression levels, to thereby selecta therapy for said patient. In a preferred embodiment step (iii) isperformed by a computer. The most similar reference profile may beselected by weighing a comparison value of the plurality using a weightvalue associated with the corresponding expression data.

In one embodiment, the invention provides a system that comprises ameans for receiving gene expression data for one or a plurality ofgenes; a means for comparing the gene expression data from each of saidone or plurality of genes to a common reference frame; and a means forpresenting the results of the comparison. This system may furthercomprise a means for clustering the data.

In another embodiment, the invention provides a computer program foranalyzing gene expression data comprising (i) a computer code thatreceives as input gene expression data for a plurality of genes and (ii)a computer code that compares said gene expression data from each ofsaid plurality of genes to a common reference frame.

The invention also provides a machine-readable or computer-readablemedium including program instructions for performing the followingsteps: (i) comparing a plurality of values corresponding to expressionlevels of one or more genes which are up- or down-regulated during boneor cartilage formation in a query cell with a database including recordscomprising reference expression of one or more reference cells and anannotation of the type of cell; and (ii) indicating to which cell thequery cell is most similar based on similarities of expression levels.

The relative levels of expression, e.g., abundance of an mRNA, in twobiological samples can be scored as a perturbation (relative abundancedifference) or as not perturbed (i.e., the relative abundance is thesame). For example, a perturbation can be a difference in expressionlevels between the two sources of RNA of at least a factor of about 25%(RNA from one source is 25% more abundant in one source than the othersource), more usually about 50%, even more often by a factor of about 2(twice as abundant), 3 (three times as abundant) or 5 (five times asabundant). Perturbations can be used by a computer for calculating andexpressing comparisons.

Preferably, in addition to identifying a perturbation as positive ornegative, it is advantageous to determine the magnitude of theperturbation. This can be carried out, as noted above, by calculatingthe ratio of the emission of the two fluorophores used for differentiallabeling, or by analogous methods that will be readily apparent to thoseof skill in the art.

The computer readable medium may further comprise a pointer to adescriptor of the level of expression or expression profile, e.g., fromwhich source it was obtained, e.g., from which patient it was obtained.A descriptor can reflect the stage of a disease, the therapy that apatient is undergoing or any other descriptions of the source ofexpression levels.

In operation, the means for receiving gene expression data, the meansfor comparing the gene expression data, the means for presenting, themeans for normalizing, and the means for clustering within the contextof the systems of the present invention can involve a programmedcomputer with the respective functionalities described herein,implemented in hardware or hardware and software; a logic circuit orother component of a programmed computer that performs the operationsspecifically identified herein, dictated by a computer program; or acomputer memory encoded with executable instructions representing acomputer program that can cause a computer to function in the particularfashion described herein.

Those skilled in the art will understand that the systems and methods ofthe present invention may be applied to a variety of systems, includingIBM-compatible personal computers running MS-DOS or Microsoft Windows.

The computer may have internal components linked to external components.The internal components may include a processor element interconnectedwith a main memory. The computer system can be an Intel Pentium®-basedprocessor of 200 MHz or greater clock rate and with 32 MB or more ofmain memory. The external component may comprise a mass storage, whichcan be one or more hard disks (which are typically packaged togetherwith the processor and memory). Such hard disks are typically of 1 GB orgreater storage capacity. Other external components include a userinterface device, which can be a monitor, together with an inputtingdevice, which can be a “mouse”, or other graphic input devices, and/or akeyboard. A printing device can also be attached to the computer.

Typically, the computer system is also linked to a network link, whichcan be part of an Ethernet link to other local computer systems, remotecomputer systems, or wide area communication networks, such as theInternet. This network link allows the computer system to share data andprocessing tasks with other computer systems.

Loaded into memory during operation of this system are several softwarecomponents, which are both standard in the art and special to theinstant invention. These software components collectively cause thecomputer system to function according to the methods of this invention.These software components are typically stored on a mass storage. Asoftware component represents the operating system, which is responsiblefor managing the computer system and its network interconnections. Thisoperating system can be, for example, of the Microsoft Windows' family,such as Windows 95, Windows 98, or Windows NT. A software componentrepresents common languages and functions conveniently present on thissystem to assist programs implementing the methods specific to thisinvention. Many high or low level computer languages can be used toprogram the analytic methods of this invention. Instructions can beinterpreted during run-time or compiled. Preferred languages includeC/C++, and JAVA®. Most preferably, the methods of this invention areprogrammed in mathematical software packages which allow symbolic entryof equations and high-level specification of processing, includingalgorithms to be used, thereby freeing a user of the need toprocedurally program individual equations or algorithms. Such packagesinclude Matlab from Mathworks (Natick, Mass.), Mathematica from WolframResearch (Champaign, Ill.), or S-Plus from Math Soft (Cambridge, Mass.).Accordingly, a software component represents the analytic methods ofthis invention as programmed in a procedural language or symbolicpackage. In a preferred embodiment, the computer system also contains adatabase comprising values representing levels of expression of one ormore genes which are up- or down-regulated during bone or cartilageformation. The database may contain one or more expression profiles ofgenes which are up- or down-regulated during bone or cartilage formationin different cells.

In an exemplary implementation, to practice the methods of the presentinvention, a user first loads expression data into the computer system.These data can be directly entered by the user from a monitor andkeyboard, or from other computer systems linked by a network connection,or on removable storage media such as a CD-ROM or floppy disk or throughthe network. Next the user causes execution of expression profileanalysis software which performs the steps of comparing and, e.g.,clustering co-varying genes into groups of genes.

In another exemplary implementation, expression profiles are comparedusing a method described in U.S. Pat. No. 6,203,987. A user first loadsexpression profile data into the computer system. Geneset profiledefinitions are loaded into the memory from the storage media or from aremote computer, preferably from a dynamic geneset database system,through the network. Next the user causes execution of projectionsoftware which performs the steps of converting expression profile toprojected expression profiles. The projected expression profiles arethen displayed.

In yet another exemplary implementation, a user first leads a projectedprofile into the memory. The user then causes the loading of a referenceprofile into the memory. Next, the user causes the execution ofcomparison software which performs the steps of objectively comparingthe profiles.

3. EXEMPLARY DIAGNOSTIC AND PROGNOSTIC COMPOSITIONS AND DEVICES OF THEINVENTION

Any composition and device (e.g., an array or microarray) for use in theabove-described methods are within the scope of the invention.

In one embodiment, the invention provides a composition comprising aplurality of detection agents for detecting expression of genes whichare up- or down-regulated during bone or cartilage formation. In apreferred embodiment, the composition comprises at least 2, preferablyat least 3, 5, 10, 20, 50, or 100 different detection agents, such as togenes listed in Tables 1, 2, 5, 6 and/or 7. In certain embodiments, thecomposition comprises at most about 1000, 500, 300, 100, 50, 30, 10, 5or 3 detection agents. Certain composition may comprise no more thanabout 1, 2, 3, 5, or 10 detection agents of genes which are not listedin Tables 1, 2, 5, 6 and/or 7. In certain compositions, less than about1%, 3%, 5%, 10%, 30% or 50% of the detection agents are to genes thatare not listed in Tables 1, 2, 5, 6 and/or 7. A detection agent can be anucleic acid probe, e.g., DNA or RNA, or it can be a polypeptide, e.g.,as antibody that binds to the polypeptide encoded by a gene that is up-or down-regulated during bone or cartilage formation. The probes can bepresent in equal amount or in different amounts in the solution.

A nucleic acid probe can be at least about 10 nucleotides long,preferably at least about 15, 20, 25, 30, 50, 100 nucleotides or more,and can comprise the full length gene. Preferred probes are those thathybridize specifically to genes listed in any of Tables 1, 2, 5, 6and/or 7. If the nucleic acid is short (i.e., 20 nucleotides or less),the sequence is preferably perfectly complementary to the target gene(i.e., a gene that is up- or down-regulated during bone or cartilageformation), such that specific hybridization can be obtained. However,nucleic acids, even short ones that are not perfectly complementary tothe target gene can also be included in a composition of the invention,e.g., for use as a negative control. Certain compositions may alsocomprise nucleic acids that are complementary to, and capable ofdetecting, an allele of a gene.

In a preferred embodiment, the invention provides nucleic acids whichhybridize under high stringency conditions of 0.2 to 1×SSC at 65° C.followed by a wash at 0.2×SSC at 65° C. to genes which are up- ordown-regulated during bone or cartilage formation. In anotherembodiment, the invention provides nucleic acids which hybridize underlow stringency conditions of 6×SSC at room temperature followed by awash at 2×SSC at room temperature. Other nucleic acids probes hybridizeto their target in 3×SSC at 40 or 50° C., followed by a wash in 1 or2×SSC at 20, 30, 40, 50, 60, or 65° C.

Nucleic acids which are at least about 80%, preferably at least about90%, even more preferably at least about 95% and most preferably atleast about 98% identical to genes which are up- or down-regulatedduring bone or cartilage formation or cDNAs thereof, complementsthereof, fragments and variants are also within the scope of theinvention.

Nucleic acid probes can be obtained by, e.g., polymerase chain reaction(PCR) amplification of gene segments from genomic DNA, cDNA (e.g., byRT-PCR), or cloned sequences. PCR primers are chosen, based on the knownsequence of the genes or cDNA, that result in amplification of uniquefragments. Computer programs can be used in the design of primers withthe required specificity and optimal amplification properties. See,e.g., Oligo version 5.0 (National Biosciences). Factors which apply tothe design and selection of primers for amplification are described, forexample, by Rylchik, W. (1993) “Selection of Primers for PolymeraseChain Reaction,” in Methods in Molecular Biology, Vol. 15, White B. ed.,Humana Press, Totowa, N.J. Sequences can be obtained from GenBank orother public sources.

Oligonucleotides of the invention may be synthesized by standard methodsknown in the art, e.g. by use of an automated DNA synthesizer (such asare commercially available from Biosearch, Applied Biosystems, etc.). Asexamples, phosphorothioate oligonucleotides may be synthesized by themethod of Stein et al. (1988, Nucl. Acids Res. 16: 3209),methylphosphonate oligonucleotides can be prepared by use of controlledpore glass polymer supports (Sarin et al., 1988, Proc. Nat. Acad. Sci.U.S.A. 85: 7448-7451), etc. In another embodiment, the oligonucleotideis a 2′-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analog (Inoue et al., 1987, FEBS Lett.215: 327-330).

“Rapid amplification of cDNA ends,” or RACE, is a PCR method that can beused for amplifying cDNAs from a number of different RNAs. The cDNAs maybe ligated to an oligonucleotide linker and amplified by PCR using twoprimers. One primer may be based on sequence from the instant nucleicacids, for which full length sequence is desired, and a second primermay comprise a sequence that hybridizes to the oligonucleotide linker toamplify the cDNA. A description of this method is reported in PCT Pub.No. WO 97/19110.

In another embodiment, the invention provides a composition comprising aplurality of agents which can detect a polypeptide encoded by a genethat is up- or down-regulated during bone or cartilage formation. Anagent can be, e.g., an antibody. Antibodies to polypeptides describedherein can be obtained commercially, or they can be produced accordingto methods known in the art.

The probes can be attached to a solid support, such as paper, membranes,filters, chips, pins or glass slides, or any other appropriatesubstrate, such as those further described herein. For example, probesof genes which are up- or down-regulated during bone or cartilageformation can be attached covalently or non covalently to membranes foruse, e.g., in dotblots, or to solids such as to create arrays, e.g.,microarrays. Exemplary solid surfaces, e.g., arrays, comprise probescorresponding to all or a portion of the genes listed in Tables 1, 2, 5,6 and/or 7. Solid surfaces may comprise at least about 1, 2, 3, 5, 10,20, 30, or 100 probes corresponding to genes listed in Tables 1, 2, 5, 6and/or 7. In certain embodiments, solid surfaces comprise less thanabout 1, 2, 3, 5, 10, 20, 30, or 100 probes corresponding to genes thatare not listed in Tables 1, 2, 5, 6 and/or 7. In certain solid surfaces,less than about 1%, 2%, 3%, 5%, 10%, 20%, 30%, or 50% of the probes areprobes that correspond to genes that are not listed in any of Tables 1,2, 5, 6 and/or 7.

The invention also provides computer-readable media and computerscomprising expression values of all or a portion of the genes set forthin Tables 1, 2, 5, 6 and/or 7 during bone and cartilage development,such as the values set forth in Tables 1, 2, 5, 6 and/or 7. The mediaand computers may comprise at least about 1, 2, 3, 5, 10, 20, 30, or 100values of genes listed in Tables 1, 2, 5, 6 and/or 7. In certainembodiments, media and computers comprise less than about 1, 2, 3, 5,10, 20, 30, or 100 values of genes that are not listed in Tables 1, 2,5, 6 and/or 7. In certain media and computers, less than about 1%, 2%,3%, 5%, 10%, 20%, 30%, or 50% of the values correspond to genes that arenot listed in Tables 1, 2, 5, 6 and/or 7.

Methods for preparing compositions and devices, e.g., computer readablemedia, are also within the scope of the invention.

4. THERAPEUTIC METHODS AND COMPOSITIONS

Up- or down-regulation of genes which have been shown to be down- andup-regulated during bone formation, respectively, can be used as atherapeutic method in various situations, e.g., diseases relating tobone and cartilage formation, such as osteodystrophy, osteohypertrophy,osteoblastoma, osteopertrusis, osteogenesis imperfecta, osteoporosis,osteopenia, osteoma and osteoblastoma; inflammatory diseases, such asrheumatoid arthritis and osteoarthritis; periodontal disease or otherteeth related diseases; hyperparathyroidism; hypercalcemia ofmalignancy; Paget's disease; osteolytic lesions produced by bonemetastasis; bone loss due to immobilization or sex hormone deficiency;wound healing and related tissue repair (e.g., burns, incisions andulcers); healing of fractures, e.g., in closed and open fracturereduction; improved fixation of artificial joints; repair of congenital,trauma induced, or oncologic resection induced craniofacial defects;tooth repair processes and plastic, e.g., cosmetic plastic, surgery.

Accordingly, in certain diseases, e.g., osteoporosis, which can betreated by stimulating bone or cartilage formation, the inventionprovides methods for stimulating bone or cartilage formation. In otherdiseases, e.g., osteodystrophy, osteohypertrophy, osteoma, osteoblastomaand cancers, which can be treated by inhibiting bone or cartilageformation, the invention provides methods for inhibiting bone orcartilage formation.

Certain genes have been shown herein to be expressed maximally indifferentiated bone cells (see, e.g., genes represented in bold anditalics in Table 1). Such genes are likely to be markers of osteoclastformation, differentiation or activity. Thus, inhibiting the expressionof one or more of these genes or reducing the activity of level of theprotein encoded thereby, will reduce osteoclast activity, and could thusbe used in treating diseases relating to excessive osteoclast activity,e.g., osteopenia, osteoporosis and erosion associated with arthritis.

In other embodiments, the invention is used for stimulating in vitroformation of bone or cartilage that can then be implanted into subjects.

In one embodiment, a therapeutic method includes increasing ordecreasing the level of expression of one or more genes whose expressionis abnormally low or high, respectively, relatively to that in a normalsubject. For example, the invention may comprise first determining thelevel of expression of one or more genes that are up- or down-regulatedduring bone or cartilage formation, e.g., genes in any of the Tablesdescribed herein, and then bringing the level of expression of the geneswhose level of expression differs from the control to about the level inthe control.

Gene expression may be normalized, i.e., brought to within a similarlevel relative to a control, by various ways. For example, geneexpression may be normalized by administering the protein that isencoded by the gene; by administering a nucleic acid encoding theprotein that is encoded by the gene; or by stimulating expression of thegene. Reducing gene expression can be achieved, e.g., by administrationof antisense, siRNA, ribozymes or aptamers directed to the gene orantibodies or other molecules that bind and, e.g., inactivate theprotein encoded by the gene.

In certain embodiments, osteogenic, cartilage-inducing or bone inducingfactors can be co-administered together with a gene-specific therapeuticto a subject. For example, a growth or differentiation factor or bonemorphogenetic protein, e.g., BMP-2 can be co-administered. Other factorsthat can be co-administered include those described in European patentapplications 148,155 and 169,016.

4.1. Methods for Confirming that Modulation of the Expression of a GeneImproves a Disease Relating to Bone or Cartilage Formation or Resorption

In one embodiment, the effect of up- or down-regulating the level ofexpression of a gene which is down- or up-regulated, respectively, in acell of a subject having a disease relating to bone or cartilageformation or resorption can be confirmed by phenotypic analysis of thecell characteristic of the disease, in particular by determining whetherthe cell adopts a phenotype that is more reminiscent of that of a normalcell than that of a cell characteristic of the disease relating to boneor cartilage formation or resorption. A “cell characteristic of adisease” also referred to as a “diseased cell” refers to a cell of asubject having a disease, which cell is affected by the disease, and istherefore different from the corresponding cell in a non-diseasedsubject. For example a cell characteristic of cancer is a cancer cell ortumor cell.

The effect on the cell can also be confirmed by measuring the level ofexpression of one or more genes which are up- or down-regulated duringbone or cartilage formation, and preferably at least about 10, or atleast about 100 genes which are up- or down-regulated during bone orcartilage formation. In a preferred embodiment, the level of expressionof a gene is modulated, and the level of expression of at least one genethat is up- or down-regulated during bone or cartilage formation isdetermined, e.g., by using a microarray having probes to the one or moregenes. If the normalization of expression of the gene results in atleast some normalization of the gene expression profile in the diseasedcell, then normalizing the expression of the gene in the subject havingthe disease is expected to improve the disease. The term “normalizationof the expression of a gene in a diseased cell” refers to bringing thelevel of expression of that gene in the diseased cell to a level that issimilar to that in the corresponding normal cell. “Normalization of thegene expression profile in a diseased cell” refers to bringing theexpression profile in a diseased cell essentially to that in thecorresponding non-diseased cell. If, however, the normalization ofexpression of the gene does not result in at least some normalization ofthe gene expression profile in the diseased cell, normalizing theexpression of the gene in a subject having a disease relating to bone orcartilage formation or resorption. is not expected to improve thedisease. In certain embodiments, the expression level of two or moregenes which are up- or down-regulated during bone or cartilage formationis modulated and the effect on the diseased cell is determined.

A preferred cell for use in these assays is a cell characteristic of adisease relating to bone or cartilage formation or resorption that canbe obtained from a subject and, e.g., established as a primary cellculture. The cell can be immortalized by methods known in the art, e.g.,by expression of an oncogene or large T antigen of SV40. Alternatively,cell lines corresponding to such a diseased cell can be used. Examplesinclude RAW cells and THP1 cells. However, prior to using such celllines, it may be preferably to confirm that the gene expression profileof the cell line corresponds essentially to that of a cellcharacteristic of a disease related to bone or cartilage formation orresorption. This can be done as described in details herein.

Modulating the expression of a gene in a cell can be achieved, e.g., bycontacting the cell with an agent that increases the level of expressionof the gene or the activity of the polypeptide encoded by the gene.Increasing the level of a polypeptide in a cell can also be achieved bytransfecting the cell, transiently or stably, with a nucleic acidencoding the polypeptide. Decreasing the expression of a gene in a cellcan be achieved by inhibiting transcription or translation of the geneor RNA, e.g., by introducing antisense nucleic acids, ribozymes orsiRNAs into the cells, or by inhibiting the activity of the polypeptideencoded by the gene, e.g., by using antibodies or dominant negativemutants. These methods are further described below in the context oftherapeutic methods.

A nucleic acid encoding a particular polypeptide can be obtained, e.g.,by RT-PCR from a cell that is known to express the gene. Primers for theRT-PCR can be derived from the nucleotide sequence of the gene encodingthe polypeptide. The nucleotide sequence of the gene is available, e.g.,in GenBank or in the publications. GenBank Accession numbers of thegenes listed in Tables 1, 2, 5, 6 and/or 7 are provided in the tables.Amplified DNA can then be inserted into an expression vector, accordingto methods known in the art and transfected into diseased cells of adisease related to bone or cartilage formation or resorption. In acontrol experiment, normal counterpart cells can also be transfected.The level of expression of the polypeptide in the transfected cells canbe determined, e.g., by electrophoresis and staining of the gel or byWestern blot using an a agent that binds the polypeptide, e.g., anantibody. The level of expression of one or more genes which are up- ordown-regulated during bone or cartilage formation. can then bedetermined in the transfected cells having elevated levels of thepolypeptide. In a preferred embodiment, the level of expression isdetermined by using a microarray. For example, RNA is extracted from thetransfected cells, and used as target DNA for hybridization to amicroarray, as further described herein.

These assays will allow the identification of genes which are up- ordown-regulated during bone or cartilage formation that can be used astherapeutic targets for developing therapeutics for diseases relating tobone or cartilage formation or resorption.

4.2. Therapeutic Methods 4.2.1. Methods for Reducing Expression of aGene or the Activity or Level of the Protein Encoded Thereby in aPatient

Genes that are expressed at higher levels in diseased cells of subjectshaving a disease relating to bone or cartilage formation or resorptionrelative to their expression level in a normal cell undergoing bone orcartilage formation may be used as therapeutic targets for treating thedisease. For example, it is possible to treat such a disease bydecreasing the level of the polypeptides in diseased cells. Similarly,where bone or cartilage formation is undesired, it may be inhibited byblocking or reducing the expression of a gene or the activity or levelof the encoded polypeptide that is modulated, e.g., up-regulated, duringnormal bone or cartilage formation. Bone and cartilage formation mayalso be stimulated by blocking or reducing the expression of a gene orthe activity or level of the encoded polypeptide that is modulated,e.g., down-regulated, during normal bone or cartilage formation.

(i) Antisense Nucleic Acids

One method for decreasing the level of expression of a gene is tointroduce into the cell antisense molecules which are complementary toat least a portion of the gene or RNA of the gene. An “antisense”nucleic acid as used herein refers to a nucleic acid capable ofhybridizing to a sequence-specific (e.g., non-poly A) portion of thetarget RNA, for example its translation initiation region, by virtue ofsome sequence complementarity to a coding and/or non-coding region. Theantisense nucleic acids of the invention can be oligonucleotides thatare double-stranded or single-stranded, RNA or DNA or a modification orderivative thereof, which can be directly administered in a controllablemanner to a cell or which can be produced intracellularly bytranscription of exogenous, introduced sequences in controllablequantities sufficient to perturb translation of the target RNA.

Preferably, antisense nucleic acids are of at least six nucleotides andare preferably oligonucleotides (ranging from 6 to about 200oligonucleotides). In specific aspects, the oligonucleotide is at least10 nucleotides, at least 15 nucleotides, at least 100 nucleotides, or atleast 200 nucleotides. The oligonucleotides can be DNA or RNA orchimeric mixtures or derivatives or modified versions thereof,single-stranded or double-stranded. The oligonucleotide can be modifiedat the base moiety, sugar moiety, or phosphate backbone. Theoligonucleotide may include other appending groups such as peptides, oragents facilitating transport across the cell membrane (see, e.g.,Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556;Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84: 648-652: PCTPublication No. WO 88/09810, published Dec. 15, 1988),hybridization-triggered cleavage agents (see, e.g., Krol et al., 1988,BioTechniques 6: 958-976) or intercalating agents (see, e.g. Zon, 1988,Pharm. Res. 5: 539-549).

In a preferred aspect of the invention, an antisense oligonucleotide isprovided, preferably as single-stranded DNA. The oligonucleotide may bemodified at any position on its structure with constituents generallyknown in the art. For example, the antisense oligonucleotides maycomprise at least one modified base moiety which is selected from thegroup including but not limited to 5-fluorouracil, 5-bromouracil,5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w,and 2,6-diaminopurine.

In another embodiment, the oligonucleotide comprises at least onemodified sugar moiety selected from the group including, but not limitedto, arabinose, 2-fluoroarabinose, xylulose, and hexose.

In yet another embodiment, the oligonucleotide comprises at least onemodified phosphate backbone selected from the group consisting of aphosphorothioate, a phosphorodithioate, a phosphoramidothioate, aphosphoramidate, a phosphordiamidate, a methylphosphonate, an alkylphosphotriester, and a formacetal or analog thereof.

In yet another embodiment, the oligonucleotide is a 2-α-anomericoligonucleotide. An α-anomeric oligonucleotide forms specificdouble-stranded hybrids with complementary RNA in which, contrary to theusual β-units, the strands run parallel to each other (Gautier et al.,1987, Nucl. Acids Res. 15:6625-6641).

The oligonucleotide may be conjugated to another molecule, e.g., apeptide, hybridization triggered cross-linking agent transport agent,hybridization-triggered cleavage agent, etc. An antisense molecule canbe a “peptide nucleic acid” (PNA). PNA refers to an antisense moleculeor anti-gene agent which comprises an oligonucleotide of at least about5 nucleotides in length linked to a peptide backbone of amino acidresidues ending in lysine. The terminal lysine confers solubility to thecomposition. PNAs preferentially bind complementary single stranded DNAor RNA and stop transcript elongation, and may be pegylated to extendtheir lifespan in the cell.

The antisense nucleic acids of the invention comprise a sequencecomplementary to at least a portion of a target RNA species. However,absolute complementarity, although preferred, is not required. Asequence “complementary to at least a portion of an RNA,” as referred toherein, means a sequence having sufficient complementarity to be able tohybridize with the RNA, forming a stable duplex; in the case ofdouble-stranded antisense nucleic acids, a single strand of the duplexDNA may thus be tested, or triplex formation may be assayed. The abilityto hybridize will depend on both the degree of complementarity and thelength of the antisense nucleic acid. Generally, the longer thehybridizing nucleic acid, the more base mismatches with a target RNA itmay contain and still form a stable duplex (or triplex, as the case maybe). One skilled in the art can ascertain a tolerable degree of mismatchby use of standard procedures to determine the melting point of thehybridized complex. The amount of antisense nucleic acid that will beeffective in the inhibiting translation of the target RNA can bedetermined by standard assay techniques.

The synthesized antisense oligonucleotides can then be administered to acell in a controlled manner. For example, the antisense oligonucleotidescan be placed in the growth environment of the cell at controlled levelswhere they may be taken up by the cell. The uptake of the antisenseoligonucleotides can be assisted by use of methods well known in theart.

In an alternative embodiment, the antisense nucleic acids of theinvention are controllably expressed intracellularly by transcriptionfrom an exogenous sequence. For example, a vector can be introduced invivo such that it is taken up by a cell, within which cell the vector ora portion thereof is transcribed, producing an antisense nucleic acid(RNA) of the invention. Such a vector would contain a sequence encodingthe antisense nucleic acid. Such a vector can remain episomal or becomechromosomally integrated, as long as it can be transcribed to producethe desired antisense RNA. Such vectors can be constructed byrecombinant DNA technology methods standard in the art. Vectors can beplasmid, viral, or others known in the art, used for replication andexpression in mammalian cells. Expression of the sequences encoding theantisense RNAs can be by any promoter known in the art to act in a cellof interest. Such promoters can be inducible or constitutive. Mostpreferably, promoters are controllable or inducible by theadministration of an exogenous moiety in order to achieve controlledexpression of the antisense oligonucleotide. Such controllable promotersinclude the Tet promoter. Other usable promoters for mammalian cellsinclude, but are not limited to: the SV40 early promoter region(Bernoist and Chambon, 1981, Nature 290: 304-310), the promotercontained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamotoet al., 1980, Cell 22: 787-797), the herpes thymidine kinase promoter(Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78: 1441-1445), theregulatory sequences of the metallothionein gene (Brinster et al., 1982,Nature 296: 39-42), etc.

Antisense therapy for a variety of cancers is in clinical phase and hasbeen discussed extensively in the literature. Reed reviewed antisensetherapy directed at the Bcl-2 gene in tumors; gene transfer-mediatedoverexpression of Bcl-2 in tumor cell lines conferred resistance to manytypes of cancer drugs. (Reed, J. C., N.C.I. (1997) 89:988-990). Thepotential for clinical development of antisense inhibitors of ras isdiscussed by Cowsert, L. M., Anti-Cancer Drug Design (1997) 12:359-371.Additional important antisense targets include leukemia (Geurtz, A. M.,Anti-Cancer Drug Design (1997) 12:341-358); human C-ref kinase (Monia,B. P., Anti-Cancer Drug Design (1997) 12:327-339); and protein kinase C(McGraw et al., Anti-Cancer Drug Design (1997) 12:315-326.

(ii) Ribozymes

In another embodiment, the level of a particular mRNA or polypeptide ina cell is reduced by introduction of a ribozyme into the cell or nucleicacid encoding such. Ribozyme molecules designed to catalytically cleavemRNA transcripts can also be introduced into, or expressed, in cells toinhibit expression of the gene (see, e.g., Sarver et al., 1990, Science247:1222-1225 and U.S. Pat. No. 5,093,246). One commonly used ribozymemotif is the hammerhead, for which the substrate sequence requirementsare minimal. Design of the hammerhead ribozyme is disclosed in Usman etal., Current Opin. Struct. Biol. (1996) 6:527-533. Usman also discussesthe therapeutic uses of ribozymes. Ribozymes can also be prepared andused as described in Long et al., FASEB J. (1993) 7:25; Symons, Ann.Rev. Biochem. (1992) 61:641; Perrotta et al., Biochem. (1992) 31:16-17;Ojwang et al., Proc. Natl. Acad. Sci. (USA) (1992) 89:10802-10806; andU.S. Pat. No. 5,254,678. Ribozyme cleavage of HIV-I RNA is described inU.S. Pat. No. 5,144,019; methods of cleaving RNA using ribozymes isdescribed in U.S. Pat. No. 5,116,742; and methods for increasing thespecificity of ribozymes are described in U.S. Pat. No. 5,225,337 andKoizumi et al., Nucleic Acid Res. (1989) 17:7059-7071. Preparation anduse of ribozyme fragments in a hammerhead structure are also describedby Koizumi et al., Nucleic Acids Res. (1989) 17:7059-7071. Preparationand use of ribozyme fragments in a hairpin structure are described byChowrira and Burke, Nucleic Acids Res. (1992) 20:2835. Ribozymes canalso be made by rolling transcription as described in Daubendiek andKool, Nat. Biotechnol. (1997) 15(3):273-277.

(iii) siRNAs

Another method for decreasing or blocking gene expression is byintroducing double stranded small interfering RNAs (siRNAs), whichmediate sequence specific mRNA degradation. RNA interference (RNAi) isthe process of sequence-specific, post-transcriptional gene silencing inanimals and plants, initiated by double-stranded RNA (dsRNA) that ishomologous in sequence to the silenced gene. In vivo, long dsRNA iscleaved by ribonuclease III to generate 21- and 22-nucleotide siRNAs. Ithas been shown that 21-nucleotide siRNA duplexes specifically suppressexpression of endogenous and heterologous genes in different mammaliancell lines, including human embryonic kidney (293) and HeLa cells(Elbashir et al. Nature 2001; 411(6836):494-8).

(iv) Triplex Formation

Gene expression can be reduced by targeting deoxyribonucleotidesequences complementary to the regulatory region of the target gene(i.e., the gene promoter and/or enhancers) to form triple helicalstructures that prevent transcription of the gene in target cells in thebody. (See generally, Helene, C. 1991, Anticancer Drug Des.,6(6):569-84; Helene, C., et al., 1992, Ann, N.Y. Acad. Sci., 660:27-36;and Maher, L. J., 1992, Bioassays 14(12):807-15).

(v) Aptamers

In a further embodiment, RNA aptamers can be introduced into orexpressed in a cell. RNA aptamers are specific RNA ligands for proteins,such as for Tat and Rev RNA (Good et al., 1997, Gene Therapy 4: 45-54)that can specifically inhibit their translation.

(vi) Dominant Negative Mutants

Another method of decreasing the biological activity of a polypeptide isby introducing into the cell a dominant negative mutant. A dominantnegative mutant polypeptide will interact with a molecule with which thepolypeptide normally interacts, thereby competing for the molecule, butsince it is biologically inactive, it will inhibit the biologicalactivity of the polypeptide. A dominant negative mutant can be createdby mutating the substrate-binding domain, the catalytic domain, or acellular localization domain of the polypeptide. Preferably, the mutantpolypeptide will be overproduced. Point mutations are made that havesuch an effect. In addition, fusion of different polypeptides of variouslengths to the terminus of a protein can yield dominant negativemutants. General strategies are available for making dominant negativemutants. See Herskowitz, Nature (1987) 329:219-222.

(vi) Use of Agents Inhibiting Transcription or Polypeptide Activity

In another embodiment, a compound decreasing the expression of the geneof interest or the activity of the polypeptide is administered to asubject having a disease relating to bone or cartilage formation orresorption, such that the level or activity of the polypeptide in thediseased cells decreases, and the disease is improved. Compounds may beknown in the art or can be identified as further described herein. Forexample, where the gene encodes a polypeptide that is a protease, theactivity of the protease can be inhibited, e.g., by a compound thatbinds an active site of the enzyme, by a compound that inhibits theinteraction of the protease with its target, or by a compound thatdecreases the stability of the protease.

4.2.2. Methods for Increasing the Expression of a Gene or the Activityor Level of the Protein Encoded Thereby in a Patient

Genes which are expressed at lower levels in diseased cells of subjectshaving a disease relating to bone or cartilage formation or resorptionrelative to their expression level in a normal cell undergoing bone orcartilage formation may be used as therapeutic targets for treating suchdiseases. For example, it may be possible to treat such a disease byincreasing the level of the polypeptides in diseased cells. Similarly,where on wishes to stimulate bone formation, one may increase the levelof expression of a gene or the activity or level of protein encoded bythe gene that is modulated, e.g., up-regulated, during bone or cartilageformation. If one wishes to inhibit bone or cartilage formation, one mayincrease the level of expression of a gene or the activity or level ofprotein encoded by the gene that is modulated, e.g., down-regulated,during bone or cartilage formation.

(i) Administration of a Nucleic Acid Encoding a Polypeptide of Interestto a Subject

In one embodiment, a nucleic acid encoding a polypeptide of interest, oran equivalent thereof, such as a functionally active fragment of thepolypeptide, is administered to a subject, such that the nucleic acidarrives at the site of the diseased cells, traverses the cell membraneand is expressed in the diseased cell.

A nucleic acid encoding a polypeptide of interest can be obtained asdescribed herein, e.g., by RT-PCR, or from publicly available DNAclones. It may not be necessary to express the full length polypeptidein a cell of a subject, and a functional fragment thereof may besufficient. Similarly, it is not necessary to express a polypeptidehaving an amino acid sequence that is identical to that of the wild-typepolypeptide. Certain amino acid deletions, additions and substitutionsare permitted, provided that the polypeptide retains most of itsbiological activity. For example, it is expected that polypeptideshaving conservative amino acid substitutions will have the same activityas the polypeptide. Polypeptides that are shorter or longer than thewild-type polypeptide or which contain from one to 20 amino aciddeletions, insertions or substitutions and which have a biologicalactivity that is essentially identical to that of the wild-typepolypeptide are referred to herein as “equivalents of the polypeptide.”Equivalent polypeptides also include polypeptides having an amino acidsequence which is at least 80%, preferably at least about 90%, even morepreferably at least about 95% and most preferably at least 98% identicalor similar to the amino acid sequence of the wild-type polypeptide.

Determining which portion of the polypeptide is sufficient for improvinga disease relating to bone or cartilage formation or which polypeptidesderived from the polypeptide are “equivalents” which can be used fortreating the disease, can be done in in vitro assays. For example,expression plasmids encoding various portions of the polypeptide can betransfected into cells, e.g., diseased cells of patients, and the effectof the expression of the portion of the polypeptide in the cells can bedetermined, e.g., by visual inspection of the phenotype of the cell orby obtaining the expression profile of the cell, as further describedherein.

Any means for the introduction of polynucleotides into mammals, human ornon-human, may be adapted to the practice of this invention for thedelivery of the various constructs of the invention into the intendedrecipient. In one embodiment of the invention, the DNA constructs aredelivered to cells by transfection, i.e., by delivery of “naked” DNA orin a complex with a colloidal dispersion system. A colloidal systemincludes macromolecule complexes, nanocapsules, microspheres, beads, andlipid-based systems including oil-in-water emulsions, micelles, mixedmicelles, and liposomes. The preferred colloidal system of thisinvention is a lipid-complexed or liposome-formulated DNA. In the formerapproach, prior to formulation of DNA, e.g., with lipid, a plasmidcontaining a transgene bearing the desired DNA constructs may first beexperimentally optimized for expression (e.g., inclusion of an intron inthe 5′ untranslated region and elimination of unnecessary sequences(Felgner, et al., Ann NY Acad Sci 126-139, 1995). Formulation of DNA,e.g. with various lipid or liposome materials, may then be effectedusing known methods and materials and delivered to the recipient mammal.See, e.g., Canonico et al, Am J Respir Cell Mol Biol 10:24-29, 1994;Tsan et al, Am J Physiol 268; Alton et al., Nat Genet. 5:135-142, 1993and U.S. Pat. No. 5,679,647 by Carson et al.

The targeting of liposomes can be classified based on anatomical andmechanistic factors. Anatomical classification is based on the level ofselectivity, for example, organ-specific, cell-specific, andorganelle-specific. Mechanistic targeting can be distinguished basedupon whether it is passive or active. Passive targeting utilizes thenatural tendency of liposomes to distribute to cells of thereticulo-endothelial system (RES) in organs, which contain sinusoidalcapillaries. Active targeting, on the other hand, involves alteration ofthe liposome by coupling the liposome to a specific ligand such as amonoclonal antibody, sugar, glycolipid, or protein, or by changing thecomposition or size of the liposome in order to achieve targeting toorgans and cell types other than the naturally occurring sites oflocalization.

The surface of the targeted delivery system may be modified in a varietyof ways. In the case of a liposomal targeted delivery system, lipidgroups can be incorporated into the lipid bilayer of the liposome inorder to maintain the targeting ligand in stable association with theliposomal bilayer. Various linking groups can be used for joining thelipid chains to the targeting ligand. Naked DNA or DNA associated with adelivery vehicle, e.g., liposomes, can be administered to several sitesin a subject (see below).

In a preferred method of the invention, the DNA constructs are deliveredusing viral vectors. The transgene may be incorporated into any of avariety of viral vectors useful in gene therapy, such as recombinantretroviruses, adenovirus, adeno-associated virus (AAV), and herpessimplex virus-1, or recombinant bacterial or eukaryotic plasmids. Whilevarious viral vectors may be used in the practice of this invention,AAV- and adenovirus-based approaches are of particular interest. Suchvectors are generally understood to be the recombinant gene deliverysystem of choice for the transfer of exogenous genes in vivo,particularly into humans.

It is possible to limit the infection spectrum of viruses by modifyingthe viral packaging proteins on the surface of the viral particle (see,for example PCT publications WO93/25234, WO94/06920, and WO94/11524).For instance, strategies for the modification of the infection spectrumof viral vectors include: coupling antibodies specific for cell surfaceantigens to envelope protein (Roux et al., (1989) PNAS USA 86:9079-9083;Julan et al., (1992) J. Gen Virol 73:3251-3255; and Goud et al., (1983)Virology 163:251-254); or coupling cell surface ligands to the viralenvelope proteins (Neda et al., (1991) J. Biol. Chem. 266:14143-14146).Coupling can be in the form of the chemical cross-linking with a proteinor other variety (e.g. lactose to convert the env protein to anasialoglycoprotein), as well as by generating fusion proteins (e.g.single-chain antibody/env fusion proteins). This technique, while usefulto limit or otherwise direct the infection to certain tissue types, andcan also be used to convert an ecotropic vector in to an amphotropicvector.

The expression of a polypeptide of interest or equivalent thereof incells of a patient to which a nucleic acid encoding the polypeptide wasadministered can be determined, e.g., by obtaining a sample of the cellsof the patient and determining the level of the polypeptide in thesample, relative to a control sample. The successful administration to apatient and expression of the polypeptide or an equivalent thereof inthe cells of the patient can be monitored by determining the expressionof at least one gene that is up- or down-regulated during bone orcartilage formation, and preferably by determining an expression profileincluding most of the genes which are up- or down-regulated during boneor cartilage formation, as described herein.

(ii) Administration of a Polypeptide of Interest to a Subject

In another embodiment, a polypeptide of interest, or an equivalent orvariant thereof, e.g., a functional fragment thereof, is administered tothe subject such that it reaches the diseased cells of a disease relatedto bone or cartilage formation or resorption, and traverses the cellularmembrane. Polypeptides can be synthesized in prokaryotes or eukaryotesor cells thereof and purified according to methods known in the art. Forexample, recombinant polypeptides can be synthesized in human cells,mouse cells, rat cells, insect cells, yeast cells, and plant cells.Polypeptides can also be synthesized in cell free extracts, e.g.,reticulocyte lysates or wheat germ extracts. Purification of proteinscan be done by various methods, e.g., chromatographic methods (see,e.g., Robert K Scopes “Protein Purification: Principles and Practice”Third Ed. Springer-Verlag, N.Y. 1994). In one embodiment, thepolypeptide is produced as a fusion polypeptide comprising an epitopetag consisting of about six consecutive histidine residues. The fusionpolypeptide can then be purified on a Ni⁺⁺ column. By inserting aprotease site between the tag and the polypeptide, the tag can beremoved after purification of the peptide on the Ni⁺⁺ column. Thesemethods are well known in the art and commercial vectors and affinitymatrices are commercially available.

Administration of polypeptides can be done by mixing them withliposomes, as described above. The surface of the liposomes can bemodified by adding molecules that will target the liposome to thedesired physiological location.

In one embodiment, a polypeptide is modified so that its rate oftraversing the cellular membrane is increased. For example, thepolypeptide can be fused to a second peptide which promotes“transcytosis,” e.g., uptake of the peptide by cells. In one embodiment,the peptide is a portion of the HIV transactivator (TAT) protein, suchas the fragment corresponding to residues 37-62 or 48-60 of TAT,portions which are rapidly taken up by cell in vitro (Green andLoewenstein, (1989) Cell 55:1179-1188). In another embodiment, theinternalizing peptide is derived from the Drosophila antennapediaprotein, or homologs thereof. The 60 amino acid long homeodomain of thehomeo-protein antennapedia has been demonstrated to translocate throughbiological membranes and can facilitate the translocation ofheterologous polypeptides to which it is couples. Thus, polypeptides canbe fused to a peptide consisting of about amino acids 42-58 ofDrosophila antennapedia or shorter fragments for transcytosis. See forexample Derossi et al. (1996) J Biol Chem 271:18188-18193; Derossi etal. (1994) J Biol Chem 269:10444-10450; and Perez et al. (1992) J CellSci 102:717-722.

(iii) Use of Agents Stimulating Transcription or Polypeptide Activity

In another embodiment, a pharmaceutical composition comprising acompound that stimulates the level of expression of a gene of interestor the activity of the polypeptide in a cell is administered to asubject, such that the level of expression of the gene or polypeptidelevel or activity in the diseased cells is increased or even restored,and the disease is improving in the subject. Compounds may be known inthe art or can be identified as further described herein. Compounds mayincrease the activity of a polypeptide by stabilizing the polypeptide.

4.3. Drug Design and Discovery of Therapeutics

The invention further provides methods for identifying therapeutics thatmodulate bone and cartilage formation. For example, therapeutics thatinhibit bone or cartilage formation can be identified by treatingprecursor cells with an agent, such as a bone morphogenetic protein,e.g., BMP-2, in the presence or absence of a test compound anddetermining whether bone or cartilage formation is inhibited or not bythe presence of the test compound. The effect on bone or cartilageformation can be measured by determining the level of expression of oneor more genes that are up- or down-regulated during bone or cartilageformation, e.g., genes set forth in Tables 1, 2, 5, 6 and/or 7. Theassay that is described in the Examples can be used in such assays.

In another embodiment, therapeutics which stimulate bone formation canbe identified by contacting precursor cells with a test compound anddetermining whether bone or cartilage formation is stimulated in thepresence of the test compound. A positive control for this assay can becells treated with an agent known to cause bone or cartilage formationor differentiation, such as BMP-2. Alternatively, gene expression levelscan be measured over a time course and the levels compared to those setforth in Tables 1, 2, 5, 6 and/or 7.

As described above, genes whose modulation of expression improve adisease related to bone or cartilage formation or resorption can be usedas targets in drug design and discovery. For example, assays can beconducted to identify molecules that modulate the expression and oractivity of genes which are up- or down-regulated during bone orcartilage formation.

In one embodiment, the invention provides methods for identifying anagonist or antagonist of a polypeptide, comprising contacting thepolypeptide with a test compound under essentially physiologicalconditions, and determining whether the test compound binds to thepolypeptide or not. In another embodiment, the invention provides amethod for identifying an agonist or antagonist of a polypeptide,comprising contacting the polypeptide with a test compound underessentially physiological conditions; and determining a biologicalactivity of the polypeptide in the presence of the test compound,wherein a higher or lower biological activity in the presence relativeto the absence of the test compound indicates that the test compound isan agonist or antagonist of the polypeptide. Other assays may be basedon a change in the polypeptide, e.g., a change in its phosphorylationlevel.

In another embodiment, an agent that modulates the expression of a genethat is up- or down-regulated during bone or cartilage formation isidentified by contacting cells expressing the gene with one or more testcompounds, and monitoring the level of expression of the gene, e.g., bydirectly or indirectly determining the level of the protein encoded bythe gene. Alternatively, compounds which modulate the expression of thegene can be identified by conducting assays using the promoter region ofa gene and screening for compounds which modify binding of proteins tothe promoter region. The nucleotide sequence of the promoter may bedescribed in a publication or available in GenBank. Alternatively, thepromoter region of the gene can be isolated, e.g., by screening agenomic library with a probe corresponding to the gene. Such methods areknown in the art.

Inhibitors of the polypeptide can also be agents which bind to thepolypeptide, and thereby prevent it from functioning normally, or whichdegrades or causes the polypeptide to be degraded. For example, such anagent can be an antibody or derivative thereof which interactsspecifically with the polypeptide. Preferred antibodies are monoclonalantibodies, humanized antibodies, human antibodies, and single chainantibodies. Such antibodies can be prepared and tested as known in theart.

If a polypeptide of interest binds to another polypeptide, drugs can bedeveloped which modulate the activity of the polypeptide by modulatingits binding to the other polypeptide (referred to herein as “bindingpartner”). Cell-free assays can be used to identify compounds which arecapable of interacting with the polypeptide or binding partner, tothereby modify the activity of the polypeptide or binding partner. Sucha compound can, e.g., modify the structure of the polypeptide or bindingpartner and thereby effect its activity. Cell-free assays can also beused to identify compounds which modulate the interaction between thepolypeptide and a binding partner. In a preferred embodiment, cell-freeassays for identifying such compounds consist essentially in a reactionmixture containing the polypeptide and a test compound or a library oftest compounds in the presence or absence of a binding partner. A testcompound can be, e.g., a derivative of a binding partner, e.g., abiologically inactive peptide, or a small molecule.

Accordingly, one exemplary screening assay of the present inventionincludes the steps of contacting the polypeptide or functional fragmentthereof or a binding partner with a test compound or library of testcompounds and detecting the formation of complexes. For detectionpurposes, the molecule can be labeled with a specific marker and thetest compound or library of test compounds labeled with a differentmarker. Interaction of a test compound with a polypeptide or fragmentthereof or binding partner can then be detected by determining the levelof the two labels after an incubation step and a washing step. Thepresence of two labels after the washing step is indicative of aninteraction.

An interaction between molecules can also be identified by usingreal-time BIA (Biomolecular Interaction Analysis, Pharmacia BiosensorAB) which detects surface plasmon resonance (SPR), an opticalphenomenon. Detection depends on changes in the mass concentration ofmacromolecules at the biospecific interface, and does not require anylabeling of interactants. In one embodiment, a library of test compoundscan be immobilized on a sensor surface, e.g., which forms one wall of amicro-flow cell. A solution containing the polypeptide, functionalfragment thereof, polypeptide analog or binding partner is then flowncontinuously over the sensor surface. A change in the resonance angle asshown on a signal recording, indicates that an interaction has occurred.This technique is further described, e.g., in BIAtechnology Handbook byPharmacia.

Another exemplary screening assay of the present invention includes thesteps of (a) forming a reaction mixture including: (i) a polypeptide ofinterest, (ii) a binding partner, and (iii) a test compound; and (b)detecting interaction of the polypeptide and the binding partner. Thepolypeptide and binding partner can be produced recombinantly, purifiedfrom a source, e.g., plasma, or chemically synthesized, as describedherein. A statistically significant change (potentiation or inhibition)in the interaction of the polypeptide and binding partner in thepresence of the test compound, relative to the interaction in theabsence of the test compound, indicates a potential agonist (mimetic orpotentiator) or antagonist (inhibitor) of the polypeptide bioactivityfor the test compound. The compounds of this assay can be contactedsimultaneously. Alternatively, the polypeptide can first be contactedwith a test compound for an appropriate amount of time, following whichthe binding partner is added to the reaction mixture. The efficacy ofthe compound can be assessed by generating dose response curves fromdata obtained using various concentrations of the test compound.Moreover, a control assay can also be performed to provide a baselinefor comparison. In the control assay, isolated and purified polypeptideor binding partner is added to a composition containing the bindingpartner or polypeptide, and the formation of a complex is quantified inthe absence of the test compound.

Complex formation between a polypeptide and a binding partner may bedetected by a variety of techniques. Modulation of the formation ofcomplexes can be quantitated using, for example, detectably labeledproteins such as radiolabeled, fluorescently labeled, or enzymaticallylabeled polypeptides or binding partners, by immunoassay, or bychromatographic detection.

For processes that rely on immunodetection for quantitating one of theproteins trapped in the complex, antibodies against the protein can beused. Alternatively, the protein to be detected in the complex can be“epitope tagged” in the form of a fusion protein which includes, inaddition to the polypeptide sequence, a second polypeptide for whichantibodies are readily available (e.g. from commercial sources). Forinstance, the GST fusion proteins described above can also be used forquantification of binding using antibodies against the GST moiety. Otheruseful epitope tags include myc-epitopes (e.g., see Ellison et al.(1991) J Biol Chem 266:21150-21157) which includes a 10-residue sequencefrom c-myc, as well as the pFLAG system (International Biotechnologies,Inc.) or the pEZZ-protein A system (Pharmacia, N.J.).

Similar assays can be used to identify compounds that bind a protein ofinterest and thereby inhibit the activity of the protein.

In another embodiment, drugs are designed or optimized by monitoring thelevel of expression of a plurality of genes, e.g., with microarrays. Inone embodiment, compounds are screened by comparing the expression levelof one or more genes which are up- or down-regulated (e.g., expressionprofile) during bone or cartilage formation in a cell, e.g., a cellcharacteristic of a disease relating to bone or cartilage formation orresorption treated with a drug, relative to their expression in areference cell, e.g., a normal cell. Optionally the expression profileis also compared to that of a cell characteristic of the disease. Thecomparisons are preferably done by introducing the gene expressionprofile data of the cell treated with the drug into a computer systemcomprising reference gene expression profiles which are stored in acomputer readable form, using appropriate algorithms. Test compoundswill be screened for those which alter the level of expression of genes,so as to bring them to a level that is similar to that in a reference ornormal cell of the same type as a cell characteristic of the disease.Compounds which are capable of normalizing the expression of at leastabout 10%, preferably at least about 20%, 50%, 70%, 80% or 90% of thegenes which are up- or down-regulated during bone or cartilageformation, are candidate therapeutics.

The efficacy of the compounds can then be tested in additional in vitroassays and in vivo, in animal models, such as the one described in theExamples. The test compound is administered to the test animal and oneor more symptoms of the disease are monitored for improvement of thecondition of the animal. Expression of one or more genes which are up-or down-regulated during bone or cartilage formation can also bemeasured before and after administration of the test compound to theanimal. A normalization of the expression of one or more of these genesis indicative of the efficiency of the compound for treating a diseaserelating to bone or cartilage formation or resorption.

The toxicity, such as resulting from a stress-related response, of acandidate therapeutic compound can be evaluated, e.g., by determiningwhether it induces the expression of genes known to be associated with atoxic response. Expression of such toxicity related genes may bedetermined in different cell types, preferably those that are known toexpress the genes. In a preferred method, microarrays are used fordetecting changes in gene expression of genes known to be associatedwith a toxic response. Changes in gene expression may be a moresensitive marker of human toxicity than routine preclinical safetystudies. It was shown, e.g., that a drug which was found not be to toxicin laboratory animals was toxic when administered to humans. When geneprofiling was studied in cells contacted with the drug, however, it wasfound that a gene, whose expression is known to correlate to livertoxicity, was expressed (see below).

Such microarrays will comprise genes which are modulated in response totoxicity or stress. An exemplary array that can be used for that purposeis the Affymetrix Rat Toxicology U34 array, which contains probes of thefollowing genes: metabolism enzymes, e.g., CYP450s, acetyltransferases,and sulfotransferases; growth factors and their receptors, e.g., IGFs,interleukins, NGTs, TGFs, and VEGT; kinases and phosphatases, e.g.,lipid kinases, MAFKs, and stress-activated kinases; nuclear receptors,e.g., retinoic acid, retinoid X and PPARs; transcription factors, e.g.,oncogenes, STATs, NF-kB, and zinc finger proteins; apoptosis genes,e.g., Bcl-2 genes, Bad, Bax, Caspases and Fas; stress response genes,e.g., heat-shock proteins and drug transporters; membrane proteins,e.g., gap-junction proteins and selectins; and cell-cycle regulators,e.g., cyclins and cyclin-associated proteins. Other genes included inthe microarrays are only known because they contain the nucleotidesequence of an EST and because they have a connection with toxicity.

In one embodiment, a drug of interest is incubated with a cell, e.g., acell in culture, the RNA is extracted, and expression of genes isanalyzed with an array containing genes which have been shown to be up-or down-regulated in response to certain toxins. The results of thehybridization are then compared to databases containing expressionlevels of genes in response to certain known toxins in certainorganisms. For example, the GeneLogic ToxExpress™ database can be usedfor that purpose. The information in this database was obtained in leastin part from the use of the Affymetrix GeneChip® rat and human probearrays with samples treated in vivo or in vitro with known toxins. Thedatabase contains levels of expression of liver genes in response toknown liver toxins. These data were obtained by treating liver samplesfrom rats treated in vivo with known toxins, and comparing the level ofexpression of numerous genes with that in rat or human primaryhepatocytes treated in vitro with the same toxin. Data profiles can beretrieved and analyzed with the GeneExpress™ database tools, which aredesigned for complex data management and analysis. As indicated on theAffymetrix (Santa Clara, Calif.) website, the GeneLogic, Inc.(Gaithersburg, Md.) has preformed proof of concept studies showing thechanges in gene expression levels can predict toxic events that were notidentified by routine preclinical safety testing. GeneLogic tested adrug that had shown no evidence of liver toxicity in rats, but thatlater showed toxicity in humans. The hybridization results using theAffymetrix GeneChip® and GeneExpress™ tools showed that the drug causedabnormal elevations of alanine aminotransferase (ALT), which indicatesliver injury, in half of the patients who had used the drug.

In one embodiment of the invention, the drug of interest is administeredto an animal, such as a mouse or a rat, at different doses. As negativecontrols, animals are administered the vehicle alone, e.g., buffer orwater. Positive controls can consist of animals treated with drugs knownto be toxic. The animals can then be sacrificed at different times,e.g., at 3, 6, and 24 hours, after administration of the drug, vehiclealone or positive control drug, mRNA extracted from a sample of theirliver; and the mRNA analyzed using arrays containing nucleic acids ofgenes which are likely to be indicative of toxicity, e.g., theAffymetrix Rat Toxicology U34 assay. The hybridization results can thenbe analyzed using computer programs and databases, as described above.

In addition, toxicity of a drug in a subject can be predicted based onthe alleles of drug metabolizing genes that are present in a subject.Accordingly, it is known that certain enzymes, e.g., cytochrome p450enzymes, i.e., CYP450, metabolize drugs, and thereby may render drugswhich are innocuous in certain subjects, toxic in others. A commerciallyavailable array containing probes of different alleles of such drugmetabolizing genes can be obtained, e.g., from Affymetrix (Santa Clara,Calif.), under the name of GeneChip® CYP450 assay.

Thus, a drug for a disease relating to bone or cartilage developmentidentified as described herein can be optimized by reducing any toxicityit may have. Compounds can be derivatized in vitro using known chemicalmethods and tested for expression of toxicity related genes. Thederivatized compounds must also be retested for normalization ofexpression levels of genes which are up- or down-regulated during boneor cartilage formation. For example, the derivatized compounds can beincubated with diseased cells of a disease relating to bone or cartilageformation or resorption, and the gene expression profile determinedusing microarrays. Thus, incubating cells with derivatized compounds andmeasuring gene expression levels with a microarray that contains thegenes which are up- or down-regulated during bone or cartilage formationand a microarray containing toxicity related genes, compounds which areeffective in treating diseases relating to bone or cartilage formationor resorption and which are not toxic can be developed. Such compoundscan further be tested in animal models as described above.

In another embodiment of the invention, a drug is developed by rationaldrug design, i.e., it is designed or identified based on informationstored in computer readable form and analyzed by algorithms. More andmore databases of expression profiles are currently being established,numerous ones being publicly available. By screening such databases forthe description of drugs affecting the expression of at least some ofthe genes which are up- or down-regulated during bone or cartilageformation in a manner similar to the change in gene expression profilefrom a cell characteristic of a disease related to bone or cartilageformation or resorption to that of a normal counterpart cell, compoundscan be identified which normalize gene expression in a cellcharacteristic of such a disease. Derivatives and analogues of suchcompounds can then be synthesized to optimize the activity of thecompound, and tested and optimized as described above.

Compounds identified by the methods described above are within the scopeof the invention. Compositions comprising such compounds, in particular,compositions comprising a pharmaceutically efficient amount of the drugin a pharmaceutically acceptable carrier are also provided. Certaincompositions comprise one or more active compounds for treating diseasesrelating to bone or cartilage development.

4.4. Exemplary Therapeutic Compositions

Therapeutic compositions include the compounds described herein, e.g.,in the context of therapeutic treatments of diseases relating to bone orcartilage formation or resorption. Therapeutic compositions may compriseone or more nucleic acids encoding a polypeptide characteristic of adisease relating to bone or cartilage formation or resorption, orequivalents thereof. The nucleic acids may be in expression vectors,e.g., viral vectors. Other compositions comprise one or morepolypeptides that are up- or down-regulated during bone or cartilageformation, or equivalents thereof. Yet other compositions comprisenucleic acids encoding antisense RNA, or ribozymes, siRNAs or RNAaptamers. Also within the scope of the invention are compositionscomprising compounds identified by the methods described herein. Thecompositions may comprise pharmaceutically acceptable excipients, andmay be contained in a device for their administration, e.g., a syringe.

4.5. Administration of Compounds and Compositions of the Invention

In a preferred embodiment, the invention provides a method for treatinga subject having a disease relating to bone or cartilage formation orresorption, comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof the invention.

4.5.1. Effective Dose

Compounds of the invention refer to small molecules, polypeptides,peptide mimetics, nucleic acids or any other molecule identified aspotentially useful for treating diseases relating to bone or cartilageformation or resorption.

Toxicity and therapeutic efficacy of compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (The Dose Lethal To 50% Of ThePopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compounds which exhibit large therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage to healthycells and, thereby, reduce side effects.

Data obtained from cell culture assays and animal studies can be used informulating a range of dosage for use in humans. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED₅₀ with little or no toxicity. The dosage may varywithin this range depending upon the dosage form employed and the routeof administration utilized. For any compound used in the method of theinvention, the therapeutically effective dose can be estimated initiallyfrom cell culture assays. A dose may be formulated in animal models toachieve a circulating plasma concentration range that includes the IC₅₀(i.e., the concentration of the test compound which achieves ahalf-maximal inhibition of symptoms) as determined in cell culture. Suchinformation can be used to more accurately determine useful doses inhumans. Levels in plasma may be measured, for example, by highperformance liquid chromatography.

4.5.2. Formulation

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers or excipients. Thus, the compoundsand their physiologically acceptable salts and solvates may beformulated for administration by, for example, injection, inhalation orinsufflation (either through the mouth or the nose) or oral, buccal,parenteral or rectal administration. In one embodiment, the compound isadministered locally, at the site where the diseased cells are present,e.g., in bone, cartilage, mesenchymal tissue, muscular tissue or in ajoint.

The compounds of the invention can be formulated for a variety of loadsof administration, including systemic and topical or localizedadministration. Techniques and formulations generally may be found inRemington's Pharmaceutical Sciences, Meade Publishing Co., Easton, Pa.For systemic administration, injection is preferred, includingintramuscular, intravenous, intraperitoneal, and subcutaneous. Forinjection, the compounds of the invention can be formulated in liquidsolutions, preferably in physiologically compatible buffers such asHank's solution or Ringer's solution. In addition, the compounds may beformulated in solid form and redissolved or suspended immediately priorto use. Lyophilized forms are also included.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges, or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulphate). The tablets may be coated by methods well known in theart. Liquid preparations for oral administration may take the form of,for example, solutions, syrups or suspensions, or they may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may be prepared by conventionalmeans with pharmaceutically acceptable additives such as suspendingagents (e.g., sorbitol syrup, cellulose derivatives or hydrogenatededible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueousvehicles (e.g., ationd oil, oily esters, ethyl alcohol or fractionatedvegetable oils); and preservatives (e.g., methyl orpropyl-p-hydroxybenzoates or sorbic acid). The preparations may alsocontain buffer salts, flavoring, coloring and sweetening agents asappropriate. Preparations for oral administration may be suitablyformulated to give controlled release of the active compound.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Administration, e.g., systemic administration, can also be bytransmucosal or transdermal means. For transmucosal or transdermaladministration, penetrants appropriate to the barrier to be permeatedare used in the formulation. Such penetrants are generally known in theart, and include, for example, for transmucosal administration bilesalts and fusidic acid derivatives. In addition, detergents may be usedto facilitate permeation. Transmucosal administration may be throughnasal sprays or using suppositories. For topical administration, thecompounds of the invention can be formulated into ointments, salves,gels, or creams as generally known in the art. A wash solution can beused locally to treat an injury or inflammation to accelerate healing.

In clinical settings, a gene delivery system for a gene of interest canbe introduced into a patient by any of a number of methods, each ofwhich is familiar in the art. For instance, a pharmaceutical preparationof the gene delivery system can be introduced systemically, e.g., byintravenous injection, and specific transduction of the protein in thetarget cells occurs predominantly from specificity of transfectionprovided by the gene delivery vehicle, cell-type or tissue-typeexpression due to the transcriptional regulatory sequences controllingexpression of the receptor gene, or a combination thereof. In otherembodiments, initial delivery of the recombinant gene is more limitedwith introduction into the subject or animal being quite localized. Forexample, the gene delivery vehicle can be introduced by catheter (seeU.S. Pat. No. 5,328,470) or by stereotactic injection (e.g., Chen et al.(1994) PNAS 91: 3054-3057). A nucleic acid, such as one encoding apolypeptide of interest or homologue thereof can be delivered in a genetherapy construct by electroporation using techniques described, forexample, by Dev et al. ((1994) Cancer Treat Rev 20:105-115). Genetherapy can be conducted in vivo or ex vivo.

The pharmaceutical preparation of the gene therapy construct or compoundof the invention can consist essentially of the gene delivery system inan acceptable diluent, or can comprise a slow release matrix in whichthe gene delivery vehicle or compound is imbedded. Alternatively, wherethe complete gene delivery system can be produced intact fromrecombinant cells, e.g., retroviral vectors, the pharmaceuticalpreparation can comprise one or more cells which produce the genedelivery system.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration.

The therapeutic method may include administering the compositiontopically, systematically, or locally as an implant or device. Whenadministered, the therapeutic composition for use in this invention is,of course, in a pyrogen-free, physiologically acceptable form. Further,the composition may desirably be encapsulated or injected in a viscousform for delivery to the site of bone, cartilage, tissue damage ordiseased cells. Topical administration may be suitable for wound healingand tissue repair. Therapeutically useful agents other than thegene-specific therapeutics which may also optionally be included in thecomposition as described above, may alternatively or additionally, beadministered simultaneously or sequentially with a composition of theinvention. The compositions of the invention may be employed inassociation with surgery. Preferably for bone and/or cartilageformation, the composition would include a matrix capable of deliveringthe therapeutics to the site of bone and/or cartilage damage or othertarget site, providing a structure for the developing bone and cartilageand optimally capable of being resorbed into the body. Such matrices maybe formed of materials presently in use for other implanted medicalapplications.

The choice of matrix material may be based on biocompatibility,biodegradability, mechanical properties, cosmetic appearance andinterface properties. The particular application of the compositions ofthe invention will define the appropriate formulation. Potentialmatrices for the compositions may be biodegradable and chemicallydefined calcium sulfate, tricalciumphosphate, hydroxyapatite, polylacticacid, polyglycolic acid and polyanhydrides. Other potential materialsare biodegradable and biologically well defined, such as bone or dermalcollagen. Further matrices are comprised of pure proteins orextracellular matrix components. Other potential matrices arenonbiodegradable and chemically defined, such as sinteredhydroxyapatite, bioglass, aluminates, or other ceramics. Matrices may becomprised of combinations of any of the above mentioned types ofmaterial, such as polylactic acid and hydroxyapatite or collagen andtricalciumphosphate. The bioceramics may be altered in composition, suchas in calcium-aluminate-phosphate and processing to alter pore size,particle size, particle shape, and biodegradability.

The dosage regimen will be determined by the attending physicianconsidering various factors which modify the action of the therapeutics,e.g. amount of bone weight desired to be formed, the site of bone damageor diseased cells, the condition of the damaged bone, the type ofdisease, the size of a wound, type of damaged tissue, the patient's age,sex, and diet, the severity of any infection, time of administration andother clinical factors. The dosage may vary with the type of matrix usedin the reconstitution and the types of therapeutics in the composition.The addition of other known growth factors, such as BMP-2 and IGF I(insulin like growth factor I), to the final composition, may alsoeffect the dosage. Progress can be monitored by periodic assessment ofbone growth and/or repair, for example, x-rays, histomorphometricdeterminations and tetracycline labeling.

5. EXEMPLARY KITS

The invention further provides kits for determining the expression levelof genes which are up- or down-regulated during bone or cartilageformation or resorption. The kits may be useful for identifying subjectsthat are predisposed to developing or who have a disease relating tobone or cartilage formation or resorption, as well as for identifyingand validating therapeutics for such diseases. In one embodiment, thekit comprises a computer readable medium on which is stored one or moregene expression profiles, e.g., of cells differentiating into bone orcartilage cells, or of diseased cells of a disease relating to bone orcartilage formation or resorption, or at least values representinglevels of expression of one or more genes which are up- ordown-regulated during bone or cartilage formation. The computer readablemedium can also comprise gene expression profiles of counterpart normalcells, such as the expression profiles set forth in Tables 1, 2, 5, 6and/or 7; diseased cells treated with a drug, and any other geneexpression profile described herein. The kit can comprise expressionprofile analysis software capable of being loaded into the memory of acomputer system.

A kit can comprise a microarray comprising probes of genes which are up-or down-regulated during bone or cartilage formation. A kit can compriseone or more probes or primers for detecting the expression level of oneor more genes which are up- or down-regulated during bone or cartilageformation and/or a solid support on which probes are attached and whichcan be used for detecting expression of one or more genes which are up-or down-regulated during bone or cartilage formation in a sample. A kitmay further comprise nucleic acid controls, buffers, and instructionsfor use.

Other kits provide compositions for treating a disease relating to boneor cartilage formation or resorption. For example, a kit may compriseone or more nucleic acids corresponding to one or more genes which areup- or down-regulated during bone or cartilage formation, e.g., for usein treating a patient having a disease relating to bone or cartilageformation or resorption. The nucleic acids can be included in a plasmidor a vector, e.g., a viral vector. Other kits comprise a polypeptideencoded by a gene that is up- or down-regulated during bone or cartilageformation or an antibody to a polypeptide. Yet other kits comprisecompounds identified herein as agonists or antagonists of genes whichare up- or down-regulated during bone or cartilage formation. Thecompositions may be pharmaceutical compositions comprising apharmaceutically acceptable excipient.

Yet other kits comprise components for the identification of drugs thatmodulate the activity of a protein encoded by a gene that is up- ordown-regulated during bone or cartilage formation. Exemplary kits maycomprise a polypeptide encoded by a gene or a nucleic acid encoding sucha polypeptide that is listed in any of the Tables described herein.

The present invention is further illustrated by the following exampleswhich should not be construed as limiting in any way. The contents ofall cited references including literature references, issued patents,published and non published patent applications as cited throughout thisapplication, as well as those listed below, are hereby expresslyincorporated by reference.

Bork, P. (1993) FEBS Lett. 327:125-130; Kothapalli, D., et al. (1998)FASEB J. 12:1151-1161; Bond, J. S. and Benyon, R. J. (1995) Protein Sci.4:1247-1261; Stocker, W., et al. (1995) Protein Sci. 4:823-840; Kessler,E., et al. (2001) J. Biol. Chem. 276: 27051-27057; Kessler, E., et al.(1996) Science 271: 360-362; Jakob, M., et al. (2001) J. Cell Biochem.81: 368-377; Hiraki, Y., et al. (1988) Biochim. Biophys. Acta 969:91-99; Scott, I. C., et al. (2000) J. Biol. Chem. 275: 30504-30511;Hansen, K., et al. (1997) FEBS Lett. 409: 195-200, 1997; Hansen, K., etal. (1997) Biochem. Biophys. Res. Commun. 241: 355-362, 1997; Jahner, D.and Hunter, T. (1991) Mol. Cell Biol. 11: 3682-3690.

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of cell biology, cell culture,molecular biology, transgenic biology, microbiology, recombinant DNA,and immunology, which are within the skill of the art. Such techniquesare explained fully in the literature. (See, for example, MolecularCloning A Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch andManiatis (Cold Spring Harbor Laboratory Press: 1989); DNA Cloning,Volumes I and II (D. N. Glover ed., 1985); Oligonucleotide Synthesis (M.J. Gait ed., 1984); Mullis et al. U.S. Pat. No. 4,683,195; Nucleic AcidHybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription AndTranslation (B. D. Hames & S. J. Higgins eds. 1984); (R. I. Freshney,Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press,1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); thetreatise, Methods In Enzymology (Academic Press, Inc., N.Y.); GeneTransfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds.,1987, Cold Spring Harbor Laboratory); Vols. 154 and 155 (Wu et al.eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer andWalker, eds., Academic Press, London, 1987); Handbook Of ExperimentalImmunology, Volumes. I-IV (D. M. Weir and C. C. Blackwell, eds., 1986)(Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).

EXAMPLES Example 1

This Example describes the identification of genes which are up- anddown-regulated during hBMP-2 induced ectopic bone formation in mousequadriceps muscles

The following animal model of ectopic bone formation was used. HumanBMP-2 (Wyeth Research Division of Wyeth Pharmaceuticals, Inc.) wasdiluted to a final concentration of 1 mg/ml in formulation buffer (0.5%sucrose, 2.5% glycine, 5 mM L-glutamic acid, 5 mM NaCl, 0.01%polysorbate 80, pH 4.5) (Wyeth Research Division of WyethPharmaceuticals, Inc., MFR00842). Female B6.CB17-Prkdc<SCID>SzJ mice(˜14 weeks of age; Jackson Lab.) were randomly assigned to either acontrol or an experimental group. Mice in the control group wereinjected with 50 μl of formulation buffer into the quadriceps muscle ofeach leg. Similarly, mice in the experimental group were injected with50 μg of recombinant human BMP-2 (hBMP-2) in formulation buffer. Carewas taken to ensure that each injection was made into the middle of themuscle mass. In both groups, three mice were used for each time point.Mice were euthanized on days 1, 2, 3, 4, 7 and 14. The entire quadricepsmuscle was removed from each leg and muscles selected for RNA analysiswere snap frozen in liquid nitrogen and stored at −80 degrees Celsius.Total RNA was prepared for each sample. Equal amounts of RNA from thethree control samples were pooled to create a single control sample foreach time point.

GeneChip (Affymetrix, San Jose, Calif.) hybridization solutions wereprepared as described previously (Lockhart, D. J., et al. (1996) NatureBiotechnol. 14:1675-1680 and Wilson, S. B., et al. (2000) Proc. Nat.Acad. Sci. USA 97:7411-7416). Murine Genome U74 chips (Affymetrix cat.#900322, 900324, 900326) were scanned with the use of protocolsrecommended by Affymetrix and data was collected/reduced with the use ofthe GeneChip 3.1 application (Affymetrix). To identify differentiallyexpressed genes, GeneChip 3.1 was used to make three separate,time-matched, comparisons between a “pooled” buffer (control) and threehBMP-2 (experimental) samples.

Changes in gene expression, for each day of the experiment, werecompiled into an Excel table. This table contained only those genes thatsatisfied the following two criteria for at least one time point of theexperiment: i) the gene was Present in either or both the control andexperimental samples; and ii) relative to the control sample, geneexpression in the experimental sample was called Increasing orDecreasing. This composite table was imported into GeneSpring 3.2.12(Silicon Genetics) for graphical analysis and for the creation of theexpression profile gene lists. Table 1 lists genes on the U74 arraysthat show at least a two-fold increase in gene expression on at leastone day of the experiment. Table 2 lists genes on the U74 arrays thatshow at least a two-fold decrease in gene expression on at least one dayof the experiment.

An expression analysis using the RNA obtained as described above wasalso conducted on another gene microarray design called Mula (WyethResearch Division of Wyeth Pharmaceuticals, Inc.). Genes which werefound to be up- or down-regulated by a factor of at least about 4 areset forth in Tables 5 and 6. The numbers represent fold change (GeneFrequency_(BMP-2)/Gene Frequency_(Buffer)) in gene expression+thestandard deviation (n=3). The genes listed in Table 6 and many otherslisted in Tables 1 and 2 do not appear to have been associated with boneor cartilage formation before.

Example 2 MMP23 and CLF-1 are Up-Regulated During Bone and CartilageFormation

Two genes which have not previously been known to be associated withbone or cartilage development appear to be up-regulated at very highlevels. The first gene is Cytokine Receptor-like Factor 1 (CLF-1) andthe second gene is Matrix MetalloProtease 23 (MMP23). Graphsrepresenting the change in gene expression of each of these genes overtime during bone formation in the above-described animal model are setforth in FIGS. 1 and 2. These graphs show that CLF-1 is maximallyup-regulated about 15 fold and MMP23 is maximally up-regulated about 40fold.

To identify cells that express MMP23 and CLF-1, in situ hybridizationwas performed on tissue sections from muscles of mice injected or notwith recombinant hBMP-2. No signal was detected with a sense orantisense probe directed against the message for CLF-1 in any cell typeor at any time point in sections from muscles injected with buffer only.In contrast, the anti-sense probe was detected in sections from muscleinjected with hBMP-2. Staining was detected at all time points in thistreatment group, and these results are summarized in Table 3. Inparticular, staining was observed in hypertrophic chondrocytes on day 7and osteoblasts and some marrow cells on day 14.

No signal was detected with a sense or antisense probe directed againstthe message for MMP23 in any cell type or at any time point in sectionsfrom muscles injected with buffer only. In contrast, the anti-senseprobe detected MMP23 mRNA in sections from muscles injected with hBMP-2.Staining was detected at all time points in this treatment group, andthese results are summarized in Table 4. Staining was observed inhypertrophic chondrocytes and osteoblasts on days 7 and 14,respectively.

TABLE 3 Summary of cells stained with an antisense probe for CLF-1 mRNA*CLF-1 mRNA Day Treatment Positive Cell 1 2 3 4 7 14 BUFFER FibroblastMacrophage Chondrocyte-like N/A N/A N/A N/A N/A N/A Chondrocyte N/A N/AN/A N/A N/A N/A Marrow cell N/A N/A N/A N/A N/A N/A Osteoblast/ N/A N/AN/A N/A N/A N/A Osteocyte HBMP-2 Fibroblast + ++ ++ ++ − − Macrophage++ + ++ ++ − − Chondrocyte-like N/A N/A N/A ++ N/A N/A Chondrocyte N/AN/A N/A N/A + N/A Marrow cell N/A N/A N/A N/A N/A + Osteoblast/ N/A N/AN/A N/A N/A + Osteocyte *Binding of sense probe was not detected ineither treatment group. N/A: Cell type not present in section. +: Slightstaining intensity ++: Mild staining intensity −: Staining not detected

TABLE 4 Summary of cells stained with an antisense probe for MMP23 mRNA*MMP23 mRNA Day Treatment Positive Cell 1 2 3 4 7 14 BUFFER FibroblastMacrophage Chondrocyte-like N/A N/A N/A N/A N/A N/A Chondrocyte N/A N/AN/A N/A N/A N/A Marrow cell N/A N/A N/A N/A N/A N/A Osteoblast/ N/A N/AN/A N/A N/A N/A Osteocyte HBMP-2 Fibroblast + − − − − − Macrophage + − −− − − Chondrocyte-like N/A N/A N/A + N/A N/A Chondrocyte N/A N/A N/AN/A + N/A Marrow cell N/A N/A N/A N/A N/A − Osteoblast/ N/A N/A N/A N/AN/A + Osteocyte *Binding of sense probe was not detected in eithertreatment group. N/A: Cell type not present in section. +: Slightstaining intensity ++: Mild staining intensity −: Staining not detected

Accordingly, the results show for the first time that CLF-1 and MMP23are expressed in cells associated with bone and cartilage. These geneswill thus be useful targets in diagnostics and in drug design fordiseases relating to bone and cartilage formation.

Example 3 Patterns of Gene Expression During Particular Phases of BoneFormation

To identify genes with a particular expression profile, genes in Tables5 and 6 were analyzed with the use of GeneSpring, a data analysisprogram (Silicon Genetics, Redwood City, Calif.). GeneSpring identifiedgenes whose time-dependent expression profiles correlated with theprofiles of an exemplar gene. The correlation was based upon theprogram's standard correlation calculation, within the “Find Similar”function, and the confidence level was set to 95%. Four exemplar genes,cysteine rich protein 61 (Cyr61), procollagen type II alpha I (Col2a1),runt related transcription factor 2 (Runx2), and cathepsin K (Ctsk),were selected because their protein products appear to be phenotypicmarkers of one or more phases of endochondral bone formation. Cyr61 is amember of the CCN family of growth factors and is believed to regulatethe proliferation and differentiation of various connective tissue celltypes. Col2a1, Runx2 and Ctsk are well-defined markers for chondrocytes,osteoblasts and osteoclasts, respectively. The four lists (one for eachexemplar gene) of genes were compiled to create Table 7 and all geneswere segregated according to their membership in either Tables 5 or 6.

The temporal patterns of gene expression (Tables 5 and 6) suggest atleast two possibilities. The first possibility for the observed temporalpatterns of gene expression is that there is some role for the geneproducts during the phase of bone formation in this model system. Thesecond possibility is that patterns similar to the profiles of theexemplar genes in FIG. 3 may reveal some degree of gene co-regulation orfunctional connections between gene products. This comparative analysiscan be made qualitatively, by a visual inspection of the time-dependentexpression profiles in Tables 5 and 6, or quantitatively.Quantitatively, a data analysis program called GeneSpring identifiedgenes having expression profiles similar those of Cyr61, Col2a1, Runx2and Ctsk and these genes are listed in Table 7. Of the four exemplargenes, the correlation with Runx2 yielded the highest number of genes.It is interesting to note that several of the Runx2-like gene productsfrom Table 5 (Bmp1, Pcolce, Col5a1 and Bgn) have been functionallylinked in earlier studies of extracellular matrix proteins. For example,bone morphogenetic protein-1 (Bmp1), a member of the astacin family ofproteases, is also known as procollagen C-proteinase and is capable ofprocessing several forms of procollagen. Procollagen C-proteinaseenhancer (Pcolce) is an extracellular matrix glycoprotein that binds toprocollagen I and enhances the proteolytic activity of Bmp1 (which isalso capable of processing procollagen, type V alpha 1 (Col5a1) andprobiglycan (Bgn). Similarly, several Runx2-like gene products fromTable 6 (Pdgfrb, Fyn and Arhb) have been functionally linked.Platelet-derived growth factor receptor beta (pdgfrb) initiates asignaling cascade when activated by ligand. PDGF-BB, one of severalligands for Pdgfrb, has been shown to be an important growth factor formany cell types, including chondrocytes. Once activated by ligand,Pdgfrb has been shown to induce the phosphorylation and activation ofFyn, a member of the Src family of protein tyrosine kinases, in porcineaortic endothelial cells. In addition, Rat-2 fibroblasts exposed to PDGFshowed an increase in rhoB (Arhb; a member of the ras gene superfamilywhose products are GTP binding proteins) gene expression.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

TABLE 1 Treatment BMP2 BMP2 BMP2 BMP2 BMP2 BMP2 Time day 01 day 02 day03 day 04 day 07 day 14 Affymetrix Avg. Fold Avg. Fold Avg. Fold Avg.Fold Avg. Fold Avg. Fold Genbank Qualifier Change Change Change ChangeChange Change Gene Name Accession # 110451_at 2.76 4.33 4.35 2.49 0.003.90 UNK_AI646968 AI646968 92315_at 2.86 0.00 6.24 8.35 0.00 3.87 SLFN4AF099977 93285_at 0.00 2.14 2.31 2.81 0.00 2.94 UNK_AI845584 AI845584103563_at 0.00 4.54 5.11 2.68 0.00 5.42 UNK_AW125713 AW125713 107566_at0.00 1.55 3.55 3.44 2.08 17.15 UNK_AI849532 AI849532 115395_at 0.00 2.233.68 2.97 0.00 2.37 UNK_AW208422 AW208422 92718_at 0.00 1.68 2.17 3.310.00 2.34 UNK_AI158810 AI158810 93975_at 0.00 1.77 2.83 3.21 0.00 3.8133 POLYPEPTIDE AI853531 [R. NORVEGICUS] 96752_at 1.65 2.58 0.00 3.130.00 2.46 ICAM1 M90551 103446_at 0.00 0.00 3.81 5.48 0.00 3.13UNK_AA959954 AA959954 104177_at 0.00 0.00 3.59 2.98 0.00 2.50UNK_AA204579 AA204579 104252_at 0.00 0.00 2.17 2.34 0.00 2.47UNK_AW123823 AW123823 108877_at 0.00 0.00 2.69 2.18 0.00 2.40UNK_AI790579 AI790579 109102_r_at 0.00 1.67 2.79 2.38 0.00 2.61UNK_AI838972 AI838972 109922_at 0.00 3.60 0.00 4.21 0.00 3.09UNK_AW122872 AW122872 112478_at 0.00 0.00 2.02 2.33 0.00 2.33UNK_AI853409 AI853409 112671_at 0.00 0.00 2.84 5.17 0.00 3.73UNK_AW122101 AW122101 113758_at 0.00 0.00 0.00 3.78 3.50 23.28UNK_AI843230 AI843230 115573_at 0.00 4.17 3.10 0.00 0.00 2.99UNK_AW047581 AW047581 130459_at 0.00 2.06 3.92 4.75 −1.78 0.00UNK_AI845691 AI845691 136655_f_at 0.00 0.00 2.87 3.14 0.00 2.39UNK_AI841502 AI841502 94354_at 0.00 0.00 0.00 2.22 0.00 3.75UNK_AI845514 AI845514 95303_at 1.49 2.01 0.00 0.00 0.00 2.63 0 AA144469

97448_at 0.00 0.00 0.00 2.66 0.00 2.62 UNK_AI845165 AI845165 100880_at0.00 0.00 0.00 2.42 0.00 4.34 UNK_AA816121 AA816121 101327_at 0.00 0.000.00 2.17 0.00 4.31 UNK_U82610 U82610 103672_at 0.00 0.00 0.00 2.19 0.002.02 UNK_AW122572 AW122572 104193_at 0.00 0.00 0.00 2.01 0.00 2.39UNK_AW047583 AW047583 104195_at 0.00 1.87 0.00 3.08 0.00 2.77UNK_AA939440 AA939440 106500_f_at 0.00 0.00 0.00 2.13 0.00 2.86UNK_AI642841 AI642841 106583_at 0.00 1.46 0.00 2.34 0.00 2.21UNK_AI851530 AI851530 106644_at 0.00 0.00 0.00 2.64 0.00 6.71UNK_AW047110 AW047110 106957_f_at 0.00 0.00 2.15 0.00 0.00 3.34UNK_AI790368 AI790368 108494_at 0.00 0.00 0.00 2.39 0.00 3.23UNK_AW123118 AW123118 109099_at 0.00 0.00 2.31 0.00 0.00 2.30UNK_AW049860 AW049860 109345_at 1.60 2.28 2.23 1.95 0.00 1.75UNK_AA711635 AA711635 112015_at 0.00 0.00 0.00 2.37 0.00 5.77UNK_AI551067 AI551067 112908_at 0.00 0.00 0.00 2.18 0.00 2.63UNK_AI849021 AI849021 113181_r_at 0.00 0.00 0.00 2.41 0.00 3.28UNK_AW125085 AW125085 113248_at 0.00 1.70 2.32 0.00 0.00 3.11UNK_AI837648 AI837648 113724_at 0.00 0.48 2.16 1.55 1.17 7.05UNK_AI848964 AI848964 113865_at 0.00 0.00 0.00 2.39 0.00 2.52UNK_AA231562 AA231562 114306_at 0.00 0.00 2.13 0.00 0.00 2.92UNK_AI593556 AI593556 114380_at 0.00 1.57 0.00 2.43 0.00 3.41UNK_AA959464 AA959464 115397_at 0.00 0.00 0.00 3.18 0.00 4.45UNK_AA727857 AA727857 115453_at 0.00 0.00 0.00 0.00 2.04 23.84UNK_AA764584 AA764584 115520_at 0.00 0.00 0.00 2.91 0.00 3.20UNK_AA163981 AA163981 115874_at 0.00 0.00 0.00 2.93 0.00 3.18UNK_AW046286 AW046286 116418_at 0.00 0.00 0.00 3.54 0.00 5.07UNK_AA839780 AA839780 117265_at 0.00 0.00 2.93 0.00 0.00 4.66UNK_AI853644 AI853644 134205_at 0.00 0.00 0.00 2.79 0.00 2.04UNK_AI482096 AI482096 134405_at 0.00 0.00 0.00 2.03 0.00 3.36UNK_AI662230 AI662230 138037_at 0.00 0.00 0.00 2.32 0.00 2.43UNK_AI851460 AI851460

92474_at 0.00 0.00 0.00 0.00 0.00 2.13 UNK_AF083497 AF083497 93153_at0.00 0.00 0.00 0.00 0.40 2.46 UNK_AW124433 AW124433 93475_at 0.00 0.000.00 0.00 0.00 2.60 UNK_AI845581 AI845581 93482_at 0.00 0.00 0.00 0.000.00 2.28 UNK_AI117835 AI117835 93647_at 0.00 0.00 0.00 0.00 0.00 3.25UNK_AI152195 AI152195 93837_at 0.00 0.00 0.00 0.00 0.00 3.92UNK_AI786089 AI786089 94347_l_at 0.00 0.00 0.00 0.00 0.00 2.23UNK_AW124044 AW124044 94352_at 0.00 0.00 0.00 0.00 0.00 2.50UNK_AI850675 AI850675 94362_at 0.00 1.77 0.00 2.00 0.00 1.81UNK_AI843682 AI843682 94364_at 0.00 0.00 0.00 0.00 0.00 2.74UNK_AI847926 AI847926 94460_at 0.00 0.00 0.00 1.78 0.00 2.16UNK_AA691445 AA691445 94471_r_at 0.00 0.00 0.00 0.00 0.00 2.86UNK_AW045974 AW045974 94512_f_at 0.00 0.00 0.00 1.95 0.00 2.91UNK_AI843210 AI843210 95165_at 0.00 0.00 0.00 0.00 0.00 3.48 0 AA409156

95914_at 0.00 0.00 0.00 0.00 0.00 2.09 UNK_AA177382 AA177382 96165_at0.00 0.00 0.00 0.00 0.00 2.08 UNK_AW125109 AW125109 96172_at 0.00 0.000.00 0.00 0.00 3.73 UNK_AA795946 AA795946 96187_at 0.00 0.00 0.00 0.000.00 2.40 UNK_AI837021 AI837021 96785_at 0.00 0.00 0.00 0.00 0.00 2.14UNK_AF110520 AF110520 96790_f_at 0.00 0.00 0.00 0.00 0.00 2.16UNK_AW125222 AW125222 96806_at 0.00 0.00 0.00 0.00 0.00 2.70UNK_AI843802 AI843802 96862_at 0.00 0.00 0.00 1.98 0.00 2.03UNK_AI848584 AI848584 96881_at 0.00 0.00 0.00 1.79 0.00 2.31UNK_AW049394 AW049394 97131_at 0.00 0.00 0.00 0.00 0.00 2.66UNK_AW124615 AW124615 97197_r_at 0.00 0.00 0.00 2.21 0.00 1.78UNK_C78850 C78850 97386_at 0.00 0.00 0.00 0.00 0.00 2.29 UNK_AI853294AI853294 97598_at 0.00 0.00 0.00 0.00 0.00 3.27 UNK_AW209139 AW20913997864_at 0.00 0.00 0.00 0.00 0.00 2.90 UNK_AW258842 AW258842 97866_at0.00 0.00 0.00 0.00 0.00 2.12 UNK_AI842858 AI842858 97944_f_at 0.00 0.000.00 0.00 0.00 3.30 UNK_AF099808 AF099808

98104_at 0.00 0.00 0.00 0.00 0.00 2.65 UNK_AI842889 AI842889 98154_at0.00 0.00 0.00 2.56 0.00 1.79 UNK_AW050133 AW050133 98572_at 0.00 0.001.76 2.55 0.00 1.86 UNK_AW122551 AW122551 98849_at 0.00 0.00 0.00 0.000.00 2.52 UNK_AI463656 AI463656 98908_at 0.00 0.00 0.00 1.67 0.00 2.04UNK_AW125510 AW125510 98988_at 0.00 0.00 0.00 2.11 0.00 1.77 0 AA61497199178_at 0.00 0.00 0.00 0.00 0.00 2.09 UNK_AI845652 AI845652

99592_f_at 0.00 0.00 0.00 0.00 0.00 2.16 UNK_AB030505 AB030505 100297_at0.00 0.00 0.00 0.00 0.00 2.38 UNK_AA693125 AA693125 100890_at 0.00 0.000.00 0.00 0.00 2.48 UNK_AI173038 AI173038 101221_at 0.00 1.67 1.61 2.100.00 1.90 0 C76746 102009_at 0.00 0.00 0.00 0.00 0.00 3.95 UNK_AI835274AI835274 102348_at 0.00 0.00 0.00 1.85 0.00 2.42 XDH AI551087 102383_at0.00 0.00 0.00 0.00 0.00 3.66 UNK_AW048977 AW048977 102863_at 0.00 0.000.00 0.00 0.00 2.16 UNK_AI550530 AI550530 103356_at 0.00 0.00 0.00 0.000.00 2.97 UNK_AI843267 AI843267

103451_at 0.00 0.00 0.00 0.00 0.00 2.30 UNK_AI835159 AI835159

103582_r_at 0.00 0.00 0.00 0.00 0.00 2.59 UNK_AI845633 AI845633103678_at 0.00 0.00 0.00 0.00 0.00 2.22 UNK_AI841139 AI841139 103697_at0.00 0.00 0.00 0.00 0.00 3.81 UNK_AW061234 AW061234 103901_at 0.00 0.000.00 0.00 0.00 2.52 UNK_AW213777 AW213777

103957_at 0.00 0.00 0.00 0.00 −2.38 2.04 Trfr X57349 104036_at 0.00 0.000.00 0.00 0.00 2.39 UNK_AI845447 AI845447 104058_at 0.00 0.00 0.00 1.820.00 2.49 UNK_AW047528 AW047528 104118_at 0.00 0.00 0.00 0.00 0.00 2.29UNK_AW123781 AW123781 104150_at 0.00 2.31 0.00 0.00 0.00 1.72UNK_AW121957 AW121957 104274_at 0.00 0.00 0.00 0.00 0.00 2.47UNK_AW124843 AW124843 104316_at 0.00 0.00 0.00 0.00 0.00 2.69UNK_AI646098 AI646098 104326_at 0.00 0.00 0.04 0.00 0.00 2.48UNK_AI838951 AI838951 104477_at 0.00 0.00 0.00 0.00 0.00 3.25UNK_AW047643 AW047643 104494_at 0.00 0.00 0.00 0.00 0.00 2.16UNK_AI642098 AI642098 104513_at 0.00 0.00 0.00 0.00 0.00 2.22 EST;unknown AA688938 104550_at 0.00 0.00 0.00 0.00 0.00 2.32 UNK_AW123273AW123273 105005_at 0.00 0.00 0.00 0.00 0.00 2.02 UNK_AI020518 AI020518105143_at 0.00 0.00 0.00 0.00 0.00 2.81 UNK_AI852801 AI852801 105159_at0.00 0.00 0.00 0.00 0.00 2.62 UNK_AI843003 AI843003 105317_at 0.00 0.000.00 0.00 0.00 2.61 UNK_AI876413 AI876413 105455_at 0.00 0.00 0.00 0.000.00 2.53 UNK_AI606142 AI606142 105554_at 0.00 0.00 0.00 0.00 0.00 2.08UNK_AA177721 AA177721 105574_l_at 0.00 0.00 0.00 2.19 0.00 1.96UNK_AA833192 AA833192

105689_r_at 0.00 0.00 0.00 0.00 0.00 2.68 UNK_AI842855 AI842855106101_at 0.00 0.00 0.00 1.63 0.00 2.91 UNK_AI853221 AI853221 106184_at0.00 0.00 0.00 0.00 0.00 2.88 UNK_AI848994 AI848994 106189_at 0.00 0.000.00 0.00 0.00 2.53 UNK_AI225382 AI225382 106262_at 0.00 0.00 0.00 0.000.00 2.08 UNK_AA914186 AA914186 106479_at 0.00 0.00 0.00 0.00 0.00 2.53UNK_AI844057 AI844057 106491_at 0.00 0.00 0.00 0.00 0.00 2.06UNK_AI957035 AI957035 106536_f_at 0.00 0.00 0.00 0.00 0.00 2.86UNK_AI786456 AI786456 106616_at 0.00 0.00 0.00 0.00 0.00 2.12UNK_AA139123 AA139123 106617_at 0.00 0.00 0.00 0.00 0.00 2.16UNK_AW123240 AW123240 106635_at 0.00 0.00 0.00 0.00 0.00 3.61UNK_AA764553 AA764553 106637_r_at 0.00 0.00 0.00 0.00 0.00 2.79UNK_AI647933 AI647933 106648_at 0.00 0.00 0.00 0.00 0.00 2.85UNK_AW045837 AW045837 106654_at 0.00 0.00 0.00 0.00 0.00 2.82UNK_AA647503 AA647503 106868_at 0.00 0.00 0.00 0.00 0.00 2.33UNK_AW048984 AW048984 106958_r_at 0.00 0.00 0.00 0.00 0.00 3.40UNK_AI790368 AI790368 107045_at 0.00 1.82 0.00 0.00 0.00 2.29UNK_AA840458 AA840458 107064_at 0.00 0.00 1.47 0.00 0.00 2.10UNK_AA645686 AA645686 107273_at 0.00 0.00 0.00 0.00 0.00 2.03UNK_AW046853 AW046853 107459_at 0.00 0.00 0.00 0.00 0.00 3.47UNK_AW049987 AW049987 107483_at 0.00 0.00 0.00 0.00 0.00 2.14UNK_AW050172 AW050172 107552_at 0.00 0.00 0.00 0.00 0.00 2.74UNK_AA711627 AA711627 107602_at 0.00 0.00 0.00 0.00 0.00 3.00UNK_AA717340 AA717340 107609_at 0.00 0.00 0.00 0.00 0.00 3.22UNK_AA137485 AA137485 107766_at 0.00 0.00 0.00 0.00 0.00 2.74UNK_AI426461 AI426461 107787_at 0.00 0.00 0.00 0.00 0.00 2.22UNK_AA755149 AA755149 107871_at 0.00 1.46 0.00 0.00 0.00 2.69UNK_AW048252 AW048252 107995_at 0.00 0.00 0.00 0.00 0.00 2.14UNK_AI845884 AI845884 108073_at 0.00 0.00 0.00 0.00 0.00 2.92UNK_AI850676 AI850676 108312_at 0.00 0.00 0.00 0.00 0.00 2.66UNK_AI593736 AI593736 108329_at 0.00 0.00 0.00 0.00 0.00 2.46UNK_AA833472 AA833472 108352_at 0.00 0.00 0.00 0.00 0.00 2.32UNK_AW061021 AW061021 108368_at 0.00 0.00 0.00 0.00 0.00 2.08UNK_AI121297 AI121297 108375_at 0.00 0.00 0.00 0.00 0.00 2.22UNK_AA982346 AA982346 108492_at 0.00 0.00 0.00 1.05 0.00 4.22UNK_AI852003 AI852003 108519_at 0.00 0.00 0.00 0.00 0.00 2.72UNK_AW212926 AW212926 108556_at 0.00 0.00 0.00 0.00 0.00 2.50UNK_AI851581 AI851581

109092_at 0.00 0.00 0.00 0.00 0.00 2.32 UNK_AA763190 AA763190 109176_at0.00 0.00 0.00 0.00 0.00 2.47 UNK_AI846059 AI846059 109326_at 0.00 0.000.00 0.00 0.00 2.72 UNK_AI837923 AI837923 109410_at 0.00 0.00 0.00 0.000.00 2.67 UNK_AW121121 AW121121 109453_at 0.00 0.00 0.00 0.00 0.00 2.98UNK_AW044905 AW044905 109561_at 0.00 0.00 0.00 1.77 0.00 2.55UNK_AA032690 AA032690 109729_at 0.00 0.00 0.00 0.00 0.00 3.09UNK_AI226312 AI226312 109747_at 0.00 0.00 0.00 0.00 0.00 2.66UNK_AW046149 AW046149 109758_at 0.00 0.00 0.00 0.00 0.00 2.07UNK_AW124910 AW124910 109785_at 0.00 0.00 0.00 0.00 0.00 2.45UNK_AW123736 AW123736 109807_f_at 0.00 0.00 0.00 0.00 0.00 2.28 TSGA12AI117666 109813_f_at 0.00 0.00 0.00 0.00 0.00 2.10 UNK_AI413781 AI413781109923_at 0.00 0.00 0.00 1.67 0.00 2.09 UNK_AA792733 AA792733

109962_at 0.00 0.00 0.00 0.00 0.00 3.36 UNK_AI314322 AI314322 109970_at0.00 0.00 0.00 0.00 0.00 2.61 UNK_AI843938 AI843938 110168_at 0.00 0.000.00 0.00 0.00 3.15 UNK_AW124258 AW124258 110331_at 0.00 0.00 0.00 0.000.00 3.16 UNK_AI851383 AI851383 110355_at 0.00 0.00 0.00 0.00 0.00 2.86UNK_AW049880 AW049880 110374_at 0.00 0.00 0.00 0.00 0.00 2.98UNK_AI851558 AI851558 110396_at 0.00 0.00 0.00 0.00 0.00 2.93UNK_AW050339 AW050339 110472_f_at 0.00 0.00 0.00 0.00 0.00 2.23UNK_AW121052 AW121052 110515_at 0.00 0.00 0.00 1.94 0.00 2.61UNK_AW123207 AW123207 110570_at 0.00 0.00 0.00 0.00 0.00 2.39UNK_AA118312 AA118312 110616_at 0.00 0.00 0.00 0.00 0.00 2.28UNK_AI646542 AI646542 110712_at 0.00 0.00 0.00 0.00 0.00 2.14UNK_AA863810 AA863810 110758_at 0.00 0.00 0.00 0.00 0.00 2.61UNK_AA915391 AA915391 110790_at 0.00 −1.32 0.00 0.00 0.00 3.19UNK_AW121879 AW121879 110833_at 0.00 0.00 0.00 0.00 0.00 2.59UNK_AI847626 AI847626 110834_at 0.00 0.00 0.00 0.00 0.00 3.53UNK_AA919801 AA919801

110852_at 0.00 0.00 0.00 1.38 0.00 2.51 UNK_AI226234 AI226234111036_f_at 0.00 0.00 0.00 0.00 0.00 3.48 UNK_AI882445 AI882445111083_at 0.00 0.00 0.00 0.00 0.00 3.25 UNK_AW122341 AW122341 111191_at0.00 0.00 0.00 0.00 0.00 3.55 UNK_AW120521 AW120521 111233_at 0.00 0.000.00 0.00 0.00 3.31 UNK_AW122352 AW122352 111309_at 0.00 0.00 0.00 0.000.00 2.88 UNK_AI181332 AI181332 111405_at 0.00 0.00 0.00 0.00 0.00 2.17UNK_AI847396 AI847396 111439_at 0.00 0.00 0.00 0.00 0.00 2.69UNK_AI591562 AI591562 111515_at 0.00 0.00 0.00 0.00 0.00 3.71UNK_AW060320 AW060320 111682_at 0.00 0.00 0.00 0.00 0.00 2.47UNK_AW229627 AW229627 111707_at 0.00 0.00 0.00 0.00 0.00 2.37UNK_AW259521 AW259521 111738_at 0.00 0.00 0.00 0.00 0.00 2.54UNK_AW121627 AW121627 111790_at 0.00 0.00 0.00 0.00 0.00 2.80UNK_AW122322 AW122322 111916_at 0.00 0.00 0.00 0.00 0.00 2.06UNK_AI841396 AI841396 111924_at 0.00 0.00 0.00 0.00 0.00 2.33UNK_AA789586 AA789586 112020_g_at 0.00 0.00 0.00 0.00 0.00 3.63UNK_AA881092 AA881092 112084_at 0.00 0.00 0.00 1.49 0.00 2.11UNK_AI662678 AI662678

112388_at 0.00 0.00 0.00 0.00 0.00 2.20 UNK_AW123069 AW123069

112802_at 0.00 0.00 0.00 0.00 0.00 2.65 UNK_AW122077 AW122077 112858_at0.00 0.00 0.00 0.00 0.00 2.94 UNK_AI854616 AI854616 112918_at 0.00 0.000.00 0.00 0.00 3.95 UNK_AI842563 AI842563 112944_at 0.00 0.00 0.00 1.460.00 2.25 UNK_AI607994 AI607994 112949_at 0.00 0.00 0.00 0.00 0.00 2.74UNK_AA915460 AA915460 113019_at 0.00 0.00 0.00 0.00 0.00 2.62UNK_AA138087 AA138087

113044_at 0.00 0.00 0.00 0.00 0.00 3.47 UNK_AA002573 AA002573 113130_at0.00 0.00 0.00 0.00 0.00 2.36 UNK_AI854014 AI854014 113131_at 0.00 0.000.00 0.00 0.00 2.71 UNK_AW047592 AW047592

113240_at 0.00 0.00 0.00 1.73 0.00 2.76 UNK_AA153179 AA153179 113246_at0.00 0.00 0.00 0.00 0.00 2.29 UNK_AI156068 AI156068 113287_at 0.00 0.000.00 0.00 0.00 3.02 UNK_AI115322 AI115322 113311_r_at 0.00 0.00 0.000.00 0.00 2.64 UNK_AA175228 AA175228 113316_at 0.00 0.00 0.00 0.00 0.003.21 UNK_AI841062 AI841062 113319_at 0.00 0.00 0.00 0.00 0.00 3.04UNK_AI786159 AI786159 113339_at 0.00 0.00 0.00 0.00 0.00 2.24UNK_AW046072 AW046072 113554_at 0.00 0.00 0.00 0.00 0.00 2.53UNK_AI840943 AI840943 113579_at 0.00 0.00 0.00 0.00 0.00 2.33UNK_AI842229 AI842229 113680_at 0.00 0.00 0.00 1.91 0.00 2.52UNK_AI846297 AI846297 113737_at 0.00 0.00 0.00 0.00 0.00 2.30UNK_AW122351 AW122351 113790_at 0.00 0.00 0.00 1.63 0.00 3.67UNK_AI194566 AI194566 114005_at 0.00 0.00 0.00 1.75 0.00 3.24UNK_AW215403 AW215403 114016_at 0.00 0.00 0.00 0.00 0.00 2.30UNK_AW124568 AW124568 114045_at 0.00 0.00 0.00 0.00 0.00 2.70UNK_AI877454 AI877454 114149_at 0.00 0.00 0.00 0.00 0.00 2.05UNK_AA596704 AA596704

114213_at 0.00 0.00 0.00 0.00 0.00 2.45 UNK_AA242681 AA242681

114281_at 0.00 0.00 0.00 1.98 0.00 5.21 UNK_AI593204 AI593204 114309_at0.00 0.00 0.00 0.00 0.00 2.11 UNK_AA716898 AA716898

114408_at 0.00 0.00 0.00 0.00 0.00 2.77 UNK_AI843543 AI843543 114463_at0.00 0.00 0.00 0.00 0.00 2.40 UNK_AI585881 AI585881 114485_at 0.00 0.000.00 1.71 0.00 2.72 UNK_AI596717 AI596717 114619_at 0.00 0.00 0.00 1.830.00 2.26 UNK_AA797871 AA797871 114686_at 0.00 0.00 0.00 0.00 0.00 2.30UNK_AW048693 AW048693 114716_at 0.00 0.00 0.00 0.00 0.00 2.26UNK_AI181770 AI181770 114752_at 0.00 −2.01 0.00 0.00 0.00 2.84UNK_AI843572 AI843572 114755_at 0.00 0.00 0.00 0.00 0.00 2.34UNK_AI844350 AI844350 114804_at 0.00 0.00 0.00 0.00 0.00 2.22 NNATAI154029

114980_at 0.00 0.00 0.00 0.00 0.00 2.28 UNK_AI854024 AI854024 115004_at0.00 0.00 0.00 0.00 0.00 2.23 UNK_AI788664 AI788664 115017_at 0.00 0.000.00 1.79 0.00 2.11 UNK_AI848298 AI848298 115058_at 0.00 0.00 0.00 0.000.00 3.62 UNK_AA756546 AA756546 115110_at 0.00 0.00 0.00 0.00 0.00 2.93UNK_AA250358 AA250358 115114_at 0.00 0.00 0.00 0.00 0.00 3.74UNK_AW047112 AW047112

115398_at 0.00 0.00 0.00 0.00 0.00 2.07 UNK_AA990038 AA990038

115664_at 0.00 0.00 0.00 0.00 0.00 2.15 UNK_AA222756 AA222756 115679_at0.00 0.00 0.00 0.00 0.00 2.09 UNK_AA174839 AA174839 115692_r_at 0.000.00 0.00 0.00 0.00 2.88 UNK_AA396015 AA396015 115741_at 0.00 0.00 0.000.00 0.00 2.52 UNK_AW125843 AW125843 116096_at 0.00 0.00 0.00 0.00 0.002.33 UNK_AA718043 AA718043

116337_at 0.00 0.00 0.00 0.00 0.00 3.22 UNK_AI390374 AI390374

116380_at 0.00 0.00 0.00 0.00 0.00 2.70 UNK_AI227104 AI227104 116408_at0.00 0.00 0.00 0.00 0.00 3.16 UNK_AI851073 AI851073

116489_r_at 0.00 0.00 0.00 0.00 0.00 2.99 UNK_AA178300 AA178300

116672_at 0.00 0.00 0.00 0.00 0.00 3.31 UNK_AA611861 AA611861 116755_at0.00 0.00 0.00 0.00 0.00 2.12 UNK_AI835947 AI835947

116936_f_at 0.00 0.00 0.00 0.00 0.00 2.55 UNK_AI847709 AI847709117043_at 0.00 0.00 0.00 0.00 0.00 2.19 UNK_AI851915 AI851915 117056_at0.00 0.00 0.00 0.00 0.00 2.24 UNK_AI837103 AI837103 117120_at 0.00 0.000.00 0.00 0.00 3.42 UNK_AW124145 AW124145 117263_at 0.00 0.00 0.00 0.000.00 2.90 UNK_AI850544 AI850544 117297_at 0.00 0.00 0.00 0.00 0.00 2.56UNK_AI846211 AI846211 117302_at 0.00 0.00 0.00 0.00 0.00 2.95UNK_AI847477 AI847477

129284_at 0.00 0.00 0.00 0.00 0.00 3.32 UNK_AA154872 AA154872 129320_at0.00 0.00 0.00 0.00 0.00 3.25 UNK_AI593773 AI593773 130499_at 0.00 −1.750.00 0.00 0.00 2.16 UNK_AW108404 AW108404 132374_at 0.00 0.00 0.00 0.000.00 2.21 UNK_AI467276 AI467276 133489_f_at 0.00 0.00 0.00 1.65 0.002.50 UNK_AI449387 AI449387 133743_at 0.00 0.00 0.00 0.00 0.00 3.92UNK_AI467607 AI467607 133851_s_at 0.00 0.00 0.00 1.80 0.00 2.39UNK_AU019736 AU019736 134141_at 0.00 0.00 0.00 0.00 0.00 3.08UNK_AA189644 AA189644 135248_at 0.00 0.00 0.00 0.00 0.00 3.48UNK_AI843905 AI843905

136580_at 0.00 1.40 0.00 2.03 0.00 1.59 UNK_AI428854 AI428854 136798_at0.00 0.00 0.00 0.00 0.00 2.31 UNK_AI536255 AI536255

137569_at 0.00 0.00 0.00 0.00 0.00 2.28 UNK_AI605650 AI605650 139200_at0.00 0.00 0.00 0.00 0.00 2.05 UNK_AW045408 AW045408 140629_s_at 0.000.00 0.00 1.28 0.00 2.38 UNK_AI506220 AI506220

140820_at 0.00 0.00 0.00 0.00 0.00 2.91 UNK_AI662586 AI662586 140840_at0.00 0.00 0.00 0.00 0.00 2.96 UNK_AI791094 AI791094 94079_at 0.00 0.000.00 0.00 0.00 2.57 homolog X61452 (Drosophila); Pnutl2 110428_at 0.000.00 0.00 1.81 0.00 2.31 UNK_AA797538 AA797538 112746_at 0.00 0.00 0.000.00 0.00 2.54 UNK_AW260381 AW260381 102873_at 0.00 0.00 0.00 1.90 0.002.96 TAP2 U60091 98859_at 0.00 0.00 0.00 7.40 5.86 101.96 tartrateresistant; M99054 Acp5 99104_at 0.00 −0.86 0.00 0.00 0.00 2.83 ACRP30U49915 98589_at 0.00 1.38 0.00 2.93 0.00 2.22 differentiation M93275related protein; Adfp 99559_at 0.00 0.00 0.00 0.00 0.00 2.62dehydrogenase U14390 family 3, subfamily A2; Aldh3a2 93354_at 0.00 0.000.00 0.00 0.00 3.14 Apoc1 Z22661 104155_f_at 0.00 0.00 0.00 0.00 0.002.14 transcription factor U19118 3; Atf3

94532_at 0.00 0.00 0.00 0.00 0.00 2.12 transporting U13841 lysosomal(vacuolar proton pump), 32 kDa; Atp6e 103205_at 0.00 0.00 0.00 7.48 7.2936.60 ATP6I AI286861 130186_f_at 0.00 0.00 0.00 0.00 0.00 2.13 ATP6IAW211999 96919_at 0.00 0.00 0.00 0.00 0.00 2.22 vacuolar proton M64298channel; Atpl 94043_at 0.00 0.00 0.00 0.00 0.00 2.47 ATP6S1- AB031290112716_at 0.00 0.00 0.00 0.00 0.00 2.06 UNK_AW122682 AW122682 94189_at0.00 0.00 0.00 0.00 0.00 2.17 BAZF AB011665 100336_s_at 0.00 0.00 0.000.00 7.91 53.48 BGLAP1 L24431

92982_at 0.00 0.00 0.00 0.00 0.00 2.65 bone morphogenetic M97017 protein8a; Bmp8a 96255_at 0.00 0.00 0.00 0.00 0.00 2.02 BNIP3L AF06739592668_at 0.00 2.99 1.99 1.78 0.00 3.12 agammaglobulinemia L10627tyrosine kinase; Btk 106304_at 0.00 0.00 0.00 0.00 0.00 2.83 C1SAW215831 112110_at 0.00 0.00 0.00 0.00 0.00 2.07 CAMKK AI843712 92642_at0.00 0.00 −2.16 0.00 −2.62 5.27 CAR2 M25944 102905_at 0.00 1.80 0.002.52 0.00 1.94 CASP11 Y13089

98498_at 0.00 0.00 0.00 1.75 0.00 2.28 CASP7 D86353 97832_at 0.00 0.000.00 0.00 0.00 2.22 CD97 AA754887 98447_at 0.00 1.36 1.37 1.74 0.00 2.25binding protein M62362 (C/EBP), alpha; Cebpa 114787_at 0.00 0.00 0.000.00 0.00 2.46 UNK_AW107224 AW107224 102027_s_at 0.00 0.00 0.00 0.000.00 2.16 CHETK AA204010 92694_at 2.21 2.77 2.17 0.00 0.00 3.52 Chi3I3M94584 99070_at 0.00 0.00 1.95 2.74 0.00 2.05 conserved helix-loop$$U12473 helix ubiquitous kinase; Chuk 137242_f_at 0.00 0.00 0.00 0.000.00 27.84 CKB AI836689 93595_at 0.00 0.00 0.00 0.00 0.00 2.11 CLN2AF111172 99413_at 2.76 5.61 2.96 3.04 2.59 16.03 CMKBR1 U29678 134879_at0.00 0.00 0.00 0.00 0.00 2.62 COL11A2 AI324726 98782_at 0.00 0.00 0.000.00 0.00 2.10 complexin 2; Cplx2 D38613 93198_at 0.00 0.00 0.00 0.000.00 3.45 colony stimulating M58288 factor 3 receptor (granulocyte);Csf3r 95608_at 0.00 1.92 2.08 3.00 0.00 2.77 CTSB AI851255 104696_at0.00 0.00 0.00 0.00 0.00 2.99 CTSE AJ009840 97336_at 0.00 −2.65 0.000.00 0.00 2.12 UNK_AJ131851 AJ131851 100069_at 0.00 0.00 0.00 0.00 0.003.27 cytochrome P450, M77497 2f2; Cyp2f2 97526_at 0.00 0.00 0.00 0.000.00 2.67 LOC55946 AW123294 101960_at 0.00 0.00 0.00 2.59 0.00 1.98D10WSU52E AI842208 114696_at 0.00 0.00 0.00 0.00 0.00 2.72 UNK_AW046335AW046335 112306_at 0.00 0.00 0.00 0.00 0.00 2.37 UNK_AW121212 AW12121292610_at 0.00 0.00 0.00 2.19 0.00 2.64 DNA segment, Chr M21332 17, humanD6S45; D17H6S45 104391_s_at 0.00 0.00 0.00 0.00 0.00 2.95 D17WSU51EAI850563

103877_at 0.00 0.00 0.00 0.00 0.00 2.28 D2WSU58E AW060485 99143_at 0.000.00 0.00 0.00 0.00 2.35 TTGN1 AA614914 113046_at 0.00 0.00 0.00 0.000.00 2.45 TTGN1 AI842091 96561_at 0.00 0.00 0.00 0.00 0.00 2.30UNK_AI157475 AI157475

97863_at 0.00 0.00 0.00 0.00 0.00 2.09 UNK_AW125274 AW125274 110406_at0.00 0.00 0.00 0.00 0.00 2.63 UNK_AA958839 AA958839 99506_at 0.00 0.000.00 0.00 0.00 2.25 DAPK2 AB018002 99025_at 0.00 0.00 0.00 0.00 0.003.32 Ala-Asp/His) box L25125 polypeptide 19; Ddx19 104371_at 0.00 0.000.00 0.00 0.00 2.06 DGAT AF078752 99881_at 0.00 0.00 0.00 0.00 0.00 3.49DKK1 AF030433 99328_at 0.00 0.00 0.00 0.00 0.00 3.37 distal-less U79738homeobox 3; Dlx3 99903_at 0.00 0.00 0.00 0.00 9.98 51.29 DMP1 AJ242625114809_at 0.00 0.00 0.00 0.00 0.00 3.58 DOKL-PENDING AW046136 94052_at0.00 0.00 0.00 0.00 0.00 2.34 DPM2 AB013360 92535_at 0.00 0.00 0.00 0.000.00 3.27 Ebf L12147 104492_at 0.00 0.00 0.00 0.00 0.00 2.18 earlyB-cell factor 3; U92702 Ebf3 102996_at 0.00 0.00 0.00 0.00 0.00 2.11lysine-rich leukemia U80227 gene; Ell 92207_at 0.00 0.00 0.00 0.00 0.003.03 elastin; Eln U08210 107900_at 0.00 0.00 0.00 2.56 0.00 2.12UNK_AW123554 AW123554 102771_at 0.00 0.00 0.00 0.00 0.00 2.62 ESETAF091628 107996_at 0.00 0.00 0.00 0.00 0.00 2.27 ESTM573010 AW049050

94307_at 0.00 0.00 0.00 0.00 0.00 3.38 fibulin 1; Fbln1 X70854 100928_at−4.16 0.00 0.00 2.21 −0.01 19.58 fibulin 2; Fbln2 X75285 102366_at 0.000.00 −5.06 −3.75 0.00 2.31 UNK_AA718169 AA718169 95295_s_at 0.00 0.000.00 0.00 0.00 2.74 FMS-like tyrosine X59398 kinase 3; Flt3 101422_at0.00 0.00 0.00 0.00 0.00 2.07 FNBP4 AW121377 92959_at 0.00 0.00 0.000.00 0.00 2.21 B-cell src-homology Z48757 tyrosine kinase; Frk 102016_at0.00 −1.46 0.00 0.00 0.00 3.68 fat specific gene 27; M61737 Fsp2794966_at 0.00 1.70 0.00 1.97 0.00 2.99 phosphate Z11911 dehydrogenase X-linked; G6pdx 100407_at 0.00 0.00 0.00 0.00 0.00 2.99 galanin; GalL38580

94813_at 0.00 0.00 0.00 0.00 0.00 2.85 growth arrest X65128 specific 1;Gas1 104597_at 0.00 0.00 3.30 2.90 0.00 6.62 GBP2 AJ007970 104134_at0.00 0.00 0.00 0.00 0.00 2.51 GDAP2 Y17851 92534_at 0.00 0.00 0.00 0.000.00 2.86 (gene U10551 overexpressed in skeletal muscle); 102968_at 0.000.00 0.00 0.00 0.00 3.69 GGTLA1 AF077765 97384_at 0.00 2.67 3.42 0.000.00 2.09 UNK_AA791012 AA791012 100514_at 0.00 0.00 0.00 0.00 0.00 2.43guanine nucleotide M63660 binding protein, alpha 13; Gna13 93080_at 0.000.00 0.00 0.00 0.00 3.13 GNG3LG AF069954 97385_at 0.00 0.00 0.00 0.000.00 2.76 GNK-PENDING AJ242909 100565_at 0.00 1.93 2.25 2.33 0.00 2.45GNPI AW123396 96553_at 0.00 2.13 3.60 0.00 0.00 1.56 G-protein coupledU39827 receptor 25; Gpcr25 100594_at 0.00 0.00 0.00 2.29 0.00 2.00glycosylphosphatidyl AB008895 inositol 1 homolog (human); Gpl1h104256_at 1.79 1.75 0.00 0.00 0.00 2.53 UNK_AI120844 AI120844102995_s_at 0.00 0.00 0.00 0.00 0.00 2.21 GZMA M13226 93092_at 0.00 1.490.00 0.00 0.00 4.62 hitstocompatibility 2, U35323 class II, locus DMa,histocompatibility 2, class II, locus Mb1, histocompatibility 2, classII, locus Mb2, proteosome (prosome, macropain) subunit, beta type 9(large multifunctional protease 2); H2- DMa, H2-DMb1, H2- 93120_f_at0.00 0.00 0.00 2.02 0.00 2.69 H2-K V00746 101876_s_at 0.00 0.00 1.962.42 0.00 2.64 UNK_M35247 M35247

101523_at 0.00 0.00 0.00 2.34 0.00 1.86 H3F3A AW046194 111423_at 0.000.00 0.00 0.00 0.00 3.30 UNK_AI852812 AI852812 100966_at 0.00 0.00 0.000.00 0.00 3.32 Hcf2 U07425 104194_at 0.00 0.00 0.00 0.00 0.00 2.51 HEPHAF082567

107620_at 0.00 0.00 0.00 0.00 0.00 2.16 HIPK1 AW125573 98038_at 0.000.00 0.00 2.31 0.00 3.06 HMG4 AF022465 93378_at 0.00 0.00 0.00 0.00 0.003.93 Hoxc8 X07439 103835_f_at 0.00 0.00 0.00 0.00 0.00 3.00 HPCAL1AF085192

96144_at 0.00 0.00 0.00 0.00 0.00 2.40 IDB4 AJ001972 104500_at 0.00 0.000.00 0.00 0.00 2.01 Idua L34111 92773_at 0.00 0.00 0.00 1.95 0.00 2.30IER5 AF079528 97409_at 0.00 0.00 2.03 3.55 0.00 2.64 interferoninducible U19119 protein 1; Ifi1 93321_at 0.00 0.00 0.00 2.88 0.00 2.59interferon activated AF022371 gene 203; Ifi203 103963_f_at 0.00 0.006.13 0.00 0.00 12.91 UNK_AA914345 AA914345 137251_f_at 0.00 0.00 0.000.00 0.00 3.68 UNK_AI449282 AI449282 94398_s_at 0.00 0.00 0.00 0.00 0.002.79 INPP5B AF040094 99034_at 0.00 0.00 0.00 0.00 0.00 2.23 IRX3 Y1500198828_at 1.64 3.70 0.00 1.93 0.00 1.84 integrin alpha M X07640 (Cd11b);Itgam 99904_at 0.00 0.00 0.00 0.00 0.00 2.18 ITGB3 AF026509

99577_at 0.00 0.00 0.00 0.00 0.00 2.21 KITL M57647 97761_f_at 0.00 0.000.00 0.00 0.00 2.29 killer cell lectin-like U10094 receptor, subfamilyA, member 7; Klra7 97762_f_at 0.00 0.00 0.00 0.00 0.00 2.56 KLRA7 U1289099993_at 0.00 0.00 0.00 0.00 0.00 2.25 leucine U77083 arylaminopeptidase1, intestinal; Lap1 104658_at 0.00 0.00 0.00 0.00 1.22 12.86 LIFR D1744496810_at 0.00 0.00 0.00 0.00 0.00 2.15 LMO2 AI154017 97980_at 0.00 0.000.00 0.00 0.00 2.54 LTBR L38423 92401_at 0.00 0.00 0.00 0.00 0.00 2.01leukotriene C4 U27195 synthase; Ltc4s 96089_at 0.00 0.00 0.00 0.00 0.002.20 UNK_AI255972 AI255972 93454_at 0.00 1.58 0.00 2.37 0.00 2.17 LY68AF081789 92216_at 4.83 3.87 2.49 0.00 0.00 1.72 MADH7 AF015260103020_s_at 0.00 0.00 0.00 0.00 0.00 2.15 MAP3K1 AI317205 101834_at 0.000.00 0.00 2.51 0.00 3.21 protein kinase 3; Z14249 Mapk3 96003_at 0.000.00 0.00 0.00 0.00 2.67 MATA1L1 AW048332 96310_at 0.00 0.00 0.00 0.000.00 2.98 MBP L07508 101070_at 0.00 0.00 0.00 0.00 0.00 2.92 MKRN1AW125438 100484_at 0.00 0.00 0.00 1.38 21.43 135.83 metalloproteinaseX66473 13; Mmp13 100414_s_at 0.00 0.00 −1.84 0.00 0.00 2.69 MPO X15313

95340_at 0.00 0.00 0.00 0.00 0.00 3.06 Mt3 M93310 102096_f_at 0.00 0.00−2.42 0.00 0.00 3.13 MUP1 AI255271 101909_f_at 0.00 0.00 −4.14 0.00 0.003.70 MUP3 M16357 101910_f_at 0.00 0.00 0.00 0.00 0.00 3.19 major urinaryprotein M16359 3; Mup3 101682_f_at 0.00 0.00 0.00 0.00 0.00 3.68 majorurinary protein M16358 4; Mup4 94122_at 7.47 3.44 2.58 0.00 −3.81 −1.94MYOC AF041335 103662_at 2.05 2.83 5.66 5.71 0.00 5.18 neutrophilcytosolic U59488 factor 4; Ncf4 97843_at 0.00 0.00 0.00 0.00 0.00 2.39UNK_AI834866 AI834866 101554_at 0.00 0.00 0.00 9.53 0.00 3.44 NFKBIAU57524 104149_at 0.00 0.00 0.00 1.87 0.00 2.95 NFKBIA AI642048 100120_at0.00 0.00 0.00 0.00 0.00 2.41 NID1 L17324 94982_f_at 0.00 0.00 0.00 0.000.00 2.13 UNK_AI852470 AI852470 97497_at 0.00 0.00 0.00 0.00 0.00 3.341, (Drosophila); Z11886 Notch1 95016_at 0.00 1.82 1.85 2.13 0.00 2.03neuropilin; Nrp D50086 100436_at 0.00 0.00 0.00 0.00 0.00 2.35 Orm1M27008 103029_at 0.00 0.00 0.00 0.00 0.00 2.74 programmed cell D86344death 4; Pdcd4 95040_at 0.00 0.00 0.00 0.00 0.00 2.02 UNK_AI840810AI840810 95079_at 0.00 0.00 0.00 0.00 0.00 3.53 PDGFRA M57683 93039_at0.00 0.00 0.00 0.00 0.00 2.50 HLS2 AF009513 96502_at 0.00 0.00 0.00 0.000.00 2.85 regulating neutral U75646 endopeptidases on the X chromosome;Phex 130145_i_at 0.00 0.00 0.00 0.00 1.36 25.36 PHEX AI481510130146_f_at 0.00 0.00 0.00 0.00 1.68 14.49 PHEX AI481510 103573_at 0.000.00 0.00 0.00 0.00 3.43 4-phosphate 5- D86176 kinase, type 1 alpha;Pip5k1a

99916_at 0.00 0.00 0.00 0.00 0.00 3.44 protein kinase C, D90242 eta;Pkch 100707_at 0.00 0.00 0.00 0.00 0.00 2.05 UNK_AF030131 AF03013197926_s_at 0.00 0.00 2.13 0.00 0.00 2.82 PPARG U10374 113154_at 0.430.00 −2.71 −1.11 −2.08 2.44 UNK_AI854500 AI854500 92904_at 0.00 0.000.00 0.00 0.00 3.09 containing 1, with U08185 ZNF domain; Prdm1110362_at 0.00 0.00 0.00 0.00 0.00 2.90 UNK_AW046410 AW046410 94085_at0.00 0.00 0.00 0.00 0.00 2.37 PRG M34603 96957_at 0.00 0.00 0.00 0.000.00 3.05 PENDING AB006463 94454_at 0.00 0.00 0.00 2.36 0.00 1.70 PRTBAF085348 101486_at 0.00 0.00 0.00 0.00 0.00 2.88 PSMB10 Y10875 93085_at0.00 3.16 6.20 5.37 0.00 6.03 PSMB9 D44456 112345_at 0.00 0.00 0.00 0.000.00 2.81 UNK_AI841610 AI841610

101932_at 0.00 0.00 0.00 2.02 0.00 3.46 PTPRE D83484 92309_i_at 0.000.00 0.00 0.00 0.00 2.50 phosphatase, X58287 receptor-type, M; Ptprm92854_at 0.00 1.77 0.00 2.37 0.00 1.82 RAS oncogene D50500 family;Rab11a 100459_at 0.00 0.00 0.00 0.00 0.00 2.57 RAD50 homolog (S.cerevisiae); U66887 Rad50 99032_at 0.00 0.00 0.00 0.00 0.00 2.73dexamethasone- AF009246 induced 1; Rasd1 104618_at 0.00 0.00 0.00 0.000.00 2.22 RBBP9 AI845819 97848_at 0.00 0.00 0.00 0.00 0.00 2.19 RBMXAJ237846 100530_at 0.00 0.00 0.00 0.00 0.00 2.57 nucleotide L07924dissociation stimulator; Rgds 97844_at 0.00 0.00 2.15 2.25 0.00 3.16protein signaling 2; U67187 Rgs2 102762_r_at 0.00 0.00 0.00 0.00 0.002.08 RHAG AF057527 100980_at 0.00 0.00 0.00 0.00 0.00 2.13Rho-associated U58512 coiled-coil forming kinase 1; Rock1 93839_at 0.000.00 0.00 0.00 0.00 2.28 RTN3 AI854888 102336_at 0.00 0.00 0.00 0.000.00 2.06 RW1 AF060565 103448_at 0.00 2.51 −4.75 −1.37 −6.47 3.81binding protein A8 M83218 (calgranulin A); S100a8 103887_at 4.41 0.00−8.99 −5.52 −6.50 5.43 binding protein A9 M83219 (calgranulin B); S100a9103715_at 0.00 0.00 0.00 0.00 0.00 3.21 scinderin; Scin U04354 101436_at0.00 0.00 3.77 3.82 0.00 6.09 cytokine B subfamily M34815 (Cys-X-Cys),member 9; Scyb9

103488_at 0.00 1.89 2.03 2.49 0.00 6.53 selectin) ligand; X91144 Selpl

96682_at 0.00 0.00 0.00 0.00 0.00 3.69 SIAT7D Y15780 102318_at 0.00 0.000.00 0.00 0.00 3.68 sialyltransferase 8 X86000 (alpha-2,8-sialytransferase) D; Siat8d 110381_at 0.00 0.00 0.00 1.54 0.00 2.32 SLAPAI120030 92582_at 0.00 0.00 0.00 0.00 0.00 2.81 solute carrier familyL42115 1, member 7; Slc1a7 103347_at 0.00 0.00 0.00 0.00 0.00 2.45UNK_AI852548 AI852548 109069_at 0.00 −2.82 −2.00 0.00 0.00 3.28 SLC39A1AI255982 98299_s_at 2.97 0.00 0.00 2.13 0.00 1.52 SLFN3 AF099974115731_at 0.00 0.00 0.00 0.00 0.00 2.37 UNK_AA896535 AA896535100422_i_at 0.00 0.00 0.00 0.00 0.00 2.96 STAT5A AJ237939 93680_at 0.000.00 0.00 0.00 0.00 2.99 STK10 D89728 100425_at 0.00 1.48 0.00 0.00 0.003.69 SYK U25685 95066_at 0.00 0.00 0.00 0.00 0.00 2.20 Taldo1 U67611103328_at 0.00 0.00 0.00 2.54 0.00 2.23 TANK U59864 98087_at 0.00 0.000.00 1.88 0.00 2.80 UNK_AW048562 AW048562 92387_at 0.00 0.00 0.00 0.000.00 2.03 synthase 1, platelet; L18868 Tbxas1

92427_at 0.00 0.00 0.00 0.00 0.00 2.71 transforming growth D25540factor, beta receptor I; Tgfbr1

113920_at −1.60 0.00 0.00 0.00 0.00 2.12 UNK_AI021069 AI021069 102906_at0.00 0.00 2.95 3.25 0.00 9.29 T-cell specific L38444 GTPase; Tgtp99602_at 0.00 1.29 0.00 2.02 0.00 1.67 TIEG AF064088 101964_at 0.00 0.00−2.16 0.00 0.00 3.47 transketolase; Tkt U05809 97893_at 0.00 0.00 0.000.00 0.00 2.01 TLP AB017697 111478_at 0.00 0.00 0.00 1.96 0.00 2.34UNK_AI047601 AI047601 96700_r_at 0.00 0.00 0.00 0.00 0.00 2.46UBL1A2-PENDING AW060594 99580_s_at 0.00 1.50 0.00 1.61 0.00 2.44 UGT1A1U16818 92760_at 0.00 5.57 3.44 0.00 0.00 4.76 WASP U42471 94704_at 2.270.00 0.00 0.00 0.00 9.98 WISP2 AF100778 97950_at 0.00 0.00 0.00 2.320.00 2.77 xanthine X75129 dehydrogenase; Xdh 98053_at 0.00 1.87 0.002.77 0.00 2.11 YWHAB AF058797 97060_at 0.00 0.00 0.00 0.00 0.00 2.95YWHAQ AW215489 93013_at 3.57 3.97 3.52 5.65 7.05 6.32 IDB2 AF07786196331_at 2.04 2.99 2.67 3.12 2.54 2.59 UNK_AI842754 AI842754 99051_at2.16 3.59 4.32 7.61 3.35 4.76 S100A4 M36579 102104_f_at 2.36 3.77 6.038.42 3.97 5.52 UNK_AI504305 AI504305 109403_at 2.15 3.73 5.34 10.02 4.3719.28 UNK_AW121933 AW121933 114810_at 2.97 9.08 11.55 9.62 8.54 4.12UNK_AI447446 AI447446 130509_at 2.64 4.77 7.87 6.94 2.24 2.18UNK_AI851996 AI851996 92810_at 0.00 3.05 4.26 5.46 10.73 9.24UNK_AI842259 AI842259 92850_at 0.00 2.42 2.43 6.71 9.75 6.66UNK_AI836446 AI836446 93548_at 0.00 2.61 2.07 3.67 4.32 2.86UNK_AW122942 AW122942 93829_at 0.00 2.05 3.42 3.58 3.28 5.01UNK_AW107884 AW107884 93842_at 0.00 2.97 3.69 7.34 12.44 11.01UNK_AI196645 AI196645 94792_at 3.10 5.07 4.52 4.71 2.76 0.00UNK_AI447305 AI447305 95102_at 0.00 2.19 2.59 3.61 3.09 3.88UNK_AW123754 AW123754 95152_g_at 0.00 3.22 2.73 3.00 4.27 4.52UNK_AW061307 AW061307 95417_at 0.00 2.59 3.27 3.18 3.80 3.54UNK_AI117848 AI117848 95466_at 0.00 5.84 6.73 4.76 5.82 4.94UNK_AI837006 AI837006 95542_at 0.00 2.62 2.69 4.54 5.75 4.80UNK_AI835858 AI835858 95543_at 0.00 3.08 3.87 4.77 4.36 4.23UNK_AI843046 AI843046 95647_f_at 0.00 2.65 2.69 3.32 3.84 4.28UNK_AI465845 AI465845 95654_at 0.00 3.23 3.45 5.80 4.72 5.58UNK_AF109905 AF109905 95673_s_at 0.00 2.31 2.83 5.79 6.60 5.31UNK_AW124113 AW124113 95749_at 0.00 2.30 2.14 5.13 4.36 3.10UNK_AW122364 AW122364 95940_f_at 1.92 3.66 5.69 6.58 4.38 7.39UNK_AW047237 AW047237 96135_at 0.00 2.38 3.85 7.06 6.16 10.09UNK_AA833425 AA833425 96168_at 0.00 3.47 4.05 3.80 5.45 3.82UNK_AI591702 AI591702 96319_at 0.00 5.82 5.05 13.49 5.11 6.19UNK_AW061324 AW061324 96333_g_at 0.00 2.97 2.46 3.17 2.53 2.19UNK_AW259199 AW259199 96784_at 0.00 4.17 5.63 6.89 5.90 3.14UNK_AW123269 AW123269 96811_at 1.20 4.20 5.77 6.75 9.85 12.17UNK_AW049806 AW049806 96834_at 0.00 2.06 2.03 3.08 3.82 4.91UNK_AI843586 AI843586 96885_at 0.00 5.55 6.66 17.42 21.15 8.95UNK_AW122271 AW122271 96886_at 0.00 3.53 3.88 3.89 3.05 3.28UNK_AW060556 AW060556 97444_at 0.00 4.08 4.33 11.02 8.47 20.65UNK_AI844520 AI844520 97527_at 0.00 4.63 5.52 9.52 8.69 5.59UNK_AA681998 AA681998 97838_at 0.00 2.19 3.16 3.46 5.45 3.88UNK_AA684508 AA684508 98076_at 0.00 2.21 3.02 6.55 5.41 5.24UNK_AI835644 AI835644 98915_at 0.00 5.42 4.17 5.26 4.08 4.94UNK_AI849082 AI849082 99849_at 0.00 2.58 2.39 3.64 2.12 4.11 UNK_C85523C85523 100116_at 0.00 3.92 4.43 5.52 8.26 3.36 UNK_AI122538 AI122538100511_at 0.00 3.60 4.84 3.90 2.10 3.63 UNK_AI154249 AI154249 101061_at0.00 2.33 2.52 5.11 5.20 4.85 UNK_AI845293 AI845293 101464_at 1.63 7.866.79 16.41 14.96 19.13 metalloproteinase; V00755 Timp 101912_at 0.004.12 4.68 7.62 13.31 6.66 UNK_AI019679 AI019679 101956_at 0.00 4.37 3.277.15 8.46 8.94 UNK_AI834849 AI834849 102056_f_at 0.00 2.01 2.37 3.494.61 4.59 UNK_AA839379 AA839379 102108_f_at 0.00 2.23 2.51 3.59 3.193.25 UNK_AI505453 AI505453 102907_at 0.00 2.60 6.00 11.32 13.64 4.29UNK_AW125043 AW125043 103017_at 0.00 2.12 3.20 5.24 4.49 20.95 D13ABB1EAI060729 103723_at 0.00 2.32 2.67 3.04 3.60 3.21 0 AA608387 104023_at0.00 2.89 3.42 5.91 4.20 5.95 UNK_AW060457 AW060457 104389_at 0.00 2.653.70 4.62 5.54 7.36 UNK_AW049360 AW049360 104464_s_at 0.00 2.24 3.4810.84 18.75 9.30 UNK_AI642389 AI642389 105606_at 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3.45 4.18UNK_AA681812 AA681812 111965_at 0.00 1.88 5.19 12.18 16.02 7.92UNK_AA869027 AA869027 112062_at 0.00 0.00 2.60 4.10 8.79 9.97UNK_AA989939 AA989939 112349_at 0.00 3.23 0.00 4.74 4.11 7.10UNK_AW048860 AW048860 112373_at 0.00 3.42 0.00 3.33 3.07 9.92UNK_AI840826 AI840826 112386_at 0.00 0.00 2.10 6.36 5.47 5.04UNK_AI838633 AI838633 112411_at 0.00 3.41 0.00 3.71 5.34 5.90UNK_AW229681 AW229681 112445_at 0.00 4.88 0.00 4.11 5.78 7.36UNK_AI156718 AI156718 112464_at 0.00 0.00 2.20 2.19 5.18 3.92UNK_AI194396 AI194396 112465_at 0.00 0.00 3.34 2.83 3.08 4.56UNK_AI226955 AI226955 112766_at 0.00 0.00 2.32 2.86 4.43 2.35UNK_AI788798 AI788798 112996_at 0.00 1.91 3.42 3.15 2.25 3.79UNK_AA170203 AA170203 113036_at 0.00 0.00 9.63 27.96 22.87 15.50UNK_AW120709 AW120709 113196_at 0.00 0.00 2.73 5.42 19.47 19.66UNK_AW124306 AW124306 113268_s_at 0.00 0.00 2.94 4.41 4.90 6.78UNK_AI835128 AI835128 113302_at 0.00 0.00 3.92 4.35 2.37 2.39UNK_AA967902 AA967902 113322_at 0.00 4.17 3.83 2.29 1.80 3.97UNK_AI116109 AI116109 113989_at 0.00 1.53 2.26 3.83 2.32 2.71UNK_AW209554 AW209554 113995_at 0.00 0.00 2.09 3.10 7.68 8.85UNK_AW061313 AW061313 114602_at 0.00 0.00 2.53 4.43 5.72 4.29UNK_AW228836 AW228836 114633_at 0.00 1.95 2.18 2.85 2.34 2.13UNK_AA895405 AA895405 114635_at 0.00 0.00 3.64 5.07 2.28 3.67UNK_AA960121 AA960121 114849_at 0.00 0.00 2.04 2.51 2.21 2.98UNK_AI462265 AI462265 115057_at 0.00 3.81 0.00 4.34 6.22 9.28UNK_AI591439 AI591439 115463_at 0.00 1.89 2.87 3.42 3.47 3.30UNK_AI118729 AI118729 115786_at 0.00 2.74 4.53 4.67 5.11 0.00UNK_AI563688 AI563688 115795_at 0.00 1.66 2.14 2.42 2.02 2.38UNK_AI851830 AI851830 115800_at 0.00 0.00 2.19 2.85 3.72 4.95UNK_AW125385 AW125385 115840_at 0.00 3.42 0.00 4.03 7.10 8.17UNK_AA756752 AA756752 116382_at 0.00 2.11 0.00 3.91 8.77 15.59UNK_AW046112 AW046112 117179_at 0.00 1.97 8.96 15.72 41.33 9.71UNK_AI852894 AI852894 130969_at 0.00 0.00 2.19 2.47 2.21 3.14UNK_AI844373 AI844373 135177_at 0.00 3.65 0.00 5.69 3.01 3.18UNK_AI882074 AI882074 135189_f_at 0.00 0.00 2.54 5.92 8.57 7.44UNK_AI481498 AI481498 135257_at 0.00 1.76 2.12 3.83 3.13 5.08UNK_AI848406 AI848406 137034_f_at 0.00 2.01 0.00 3.48 3.35 3.21UNK_AI480781 AI480781 137656_s_at 2.10 4.17 0.00 3.83 1.46 2.66UNK_AI195998 AI195998 92268_at 0.00 0.00 0.00 2.96 2.58 2.60UNK_AI854851 AI854851 92279_at 0.00 0.00 0.00 3.35 3.86 2.45UNK_AW121320 AW121320 92831_at 0.00 1.64 0.00 2.11 2.74 4.13UNK_AI846308 AI846308 93174_at 0.00 0.00 0.00 3.77 9.21 14.95UNK_AI593640 AI593640 93236_s_at 0.00 1.84 2.29 2.54 3.78 1.95thymidylate M13352 synthase; Tyms 93443_at 0.00 −1.73 0.00 2.28 4.612.81 UNK_AW212271 AW212271 93472_at 0.00 0.00 0.00 5.12 7.16 5.99UNK_AA796989 AA796989 93714_f_at 0.00 0.00 0.00 2.75 2.14 2.74UNK_AI117211 AI117211 93747_at 0.00 0.00 0.00 2.11 2.53 2.90UNK_AW122599 AW122599 93830_at 0.00 0.00 0.00 2.26 2.94 2.21UNK_AI851199 AI851199 93831_at 0.00 0.00 0.00 2.37 3.09 2.39UNK_AI316087 AI316087 93974_at 0.00 0.00 1.65 4.60 2.63 5.21 33POLYPEPTIDE AW212475 [R. 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0.00 0.00 4.01 0.00UNK_AI551083 AI551083 110015_at 0.00 0.00 0.00 0.00 2.46 0.00UNK_AI385637 AI385637 110128_at 0.00 0.00 0.00 0.00 1.66 2.28UNK_AI664407 AI664407 110184_at 0.00 0.00 2.39 0.00 1.96 0.00UNK_AW123961 AW123961 110204_at 0.00 0.00 0.00 0.00 1.79 2.89UNK_AW123924 AW123924 110341_at 0.00 0.00 0.00 0.00 2.26 0.00UNK_AI851727 AI851727 110344_at 0.00 0.00 0.00 0.00 5.37 0.00UNK_AW123792 AW123792 110422_at 0.00 0.00 0.00 0.00 2.24 0.00UNK_AA896206 AA896206 110449_f_at 0.00 0.00 0.00 1.33 1.85 2.18UNK_AI154580 AI154580 110541_at 0.00 0.00 0.00 0.00 1.90 2.62UNK_AI643915 AI643915 110650_at 0.00 0.00 0.00 0.00 1.72 2.11UNK_AA959574 AA959574 110689_at 0.00 0.00 0.00 0.00 2.46 0.00 ADSLAI391284 110693_at 0.00 0.00 0.00 0.00 2.41 0.00 UNK_AW121941 AW121941110719_at 0.00 0.00 0.00 2.30 0.00 0.00 UNK_AI839189 AI839189 110824_at0.00 0.00 0.00 0.00 2.62 0.00 UNK_AW121315 AW121315 110830_at 0.00 1.670.00 2.06 0.00 0.00 UNK_AI021707 AI021707 111203_at 0.00 0.00 0.00 0.002.25 0.00 UNK_AI614021 AI614021 111262_at 0.00 0.00 0.00 0.00 1.91 2.61UNK_AW061180 AW061180 111294_at 0.00 1.68 0.00 0.00 1.89 3.19UNK_AA175446 AA175446 111312_at 0.00 0.00 0.00 0.00 3.20 0.00UNK_AA693306 AA693306 111319_at 0.00 0.00 0.00 2.37 0.00 0.00UNK_AW124761 AW124761 111322_at 0.00 0.00 0.00 0.00 1.52 2.36UNK_AI842842 AI842842 111343_i_at 0.00 0.00 0.00 2.05 1.92 0.00UNK_AI853582 AI853582 111352_at 0.00 0.00 0.00 2.36 1.72 0.00UNK_AW215724 AW215724 111379_at 0.00 0.00 0.00 2.26 1.74 0.00UNK_AI846352 AI846352 111397_at 0.00 0.00 0.00 0.00 3.13 0.00UNK_AI844734 AI844734 111417_at 0.00 0.00 0.00 0.00 2.29 0.00UNK_AA980507 AA980507 111428_at 0.00 0.00 0.00 0.00 3.95 0.00UNK_AW226863 AW226863 111430_r_at 0.00 0.00 0.00 0.00 3.43 0.00UNK_AW011836 AW011836 111459_at 0.00 0.00 0.00 0.00 5.62 0.00UNK_AI429433 AI429433 111475_at 0.00 0.00 0.00 1.97 2.16 0.00UNK_AA880439 AA880439 111533_at 0.00 0.00 0.00 0.00 3.92 1.16UNK_AI843308 AI843308 111535_at 0.00 0.00 0.00 0.00 2.17 0.00UNK_AI226156 AI226156 111543_at 0.00 0.00 0.00 0.00 2.28 0.00UNK_AW122303 AW122303 111572_at 0.00 0.00 0.00 0.00 2.53 0.00UNK_AA096501 AA096501 111578_at 0.00 0.00 0.00 1.97 2.98 0.00UNK_AA110885 AA110885 111647_at 0.00 3.03 0.00 0.00 0.00 0.00UNK_AI156274 AI156274 111685_at 0.00 0.00 0.00 0.00 3.14 0.00UNK_AW228742 AW228742 111741_at 0.00 0.00 0.00 2.39 0.00 0.00UNK_AW123268 AW123268 111772_at 0.00 0.00 0.00 0.00 3.96 0.00UNK_AI122096 AI122096 111793_at 0.00 0.00 0.00 0.00 1.64 2.34UNK_AA940547 AA940547 111800_at 0.00 0.00 0.00 0.00 1.63 2.14UNK_AI839784 AI839784 111829_at 0.00 0.00 0.00 2.17 0.00 0.00UNK_AW122867 AW122867 111850_at 0.00 1.74 0.00 0.00 3.22 0.00UNK_AI839747 AI839747 111931_at 0.00 0.00 0.00 0.00 1.81 2.75UNK_AW125297 AW125297 111939_at 0.00 0.00 0.00 0.00 2.02 0.00UNK_AI286751 AI286751 111952_at 0.00 0.00 0.00 6.16 0.00 0.00UNK_AW046394 AW046394 112018_at 0.00 0.00 0.00 1.59 2.06 0.00UNK_AW049226 AW049226 112031_g_at 0.00 0.00 0.00 0.00 2.04 0.00UNK_AW048852 AW048852 112032_at 0.00 0.00 0.00 0.00 1.43 4.48UNK_AI838644 AI838644 112082_at 0.00 0.00 0.00 0.00 5.39 0.00UNK_AI591941 AI591941 112091_at 0.00 0.00 0.00 0.00 4.52 0.00UNK_AI426016 AI426016 112167_f_at 0.00 0.00 0.00 0.00 2.50 0.00UNK_W96857 W96857 112209_at 0.00 0.00 0.00 0.00 2.64 0.00 UNK_AW122818AW122818 112269_at 0.00 0.00 0.00 0.00 1.77 2.67 UNK_AW123962 AW123962112291_r_at 0.00 1.64 1.80 0.00 2.57 1.43 UNK_AA655542 AA655542112333_at 0.00 0.00 0.00 2.17 0.00 0.00 UNK_AI835570 AI835570 112338_at0.00 0.00 0.00 0.00 3.04 0.00 UNK_AI846227 AI846227 112402_at 0.00 0.000.00 0.00 2.30 0.00 UNK_AW045953 AW045953 112404_at 0.00 0.00 0.00 0.002.70 0.00 UNK_AI844302 AI844302 112488_at 0.00 0.00 0.00 0.00 1.88 3.93UNK_AW120970 AW120970 112499_at 0.00 0.00 0.00 0.00 4.01 0.00UNK_AI172791 AI172791 112652_at 0.00 0.00 0.00 0.00 3.04 0.00UNK_AA636643 AA636643 112703_at 0.00 0.00 0.00 0.00 2.26 0.00UNK_AI846613 AI846613 112729_at 0.00 0.00 0.00 0.00 1.50 2.17UNK_AA644819 AA644819 112733_at 0.00 4.52 0.00 0.00 0.00 0.00UNK_AW212343 AW212343 112795_at 0.00 0.00 0.00 1.99 1.74 2.51UNK_AI854434 AI854434 112827_at 0.00 0.00 0.00 2.50 0.00 0.00UNK_AI847696 AI847696 112847_at 0.00 0.00 0.00 0.00 5.12 0.00UNK_AW123508 AW123508 112857_g_at 0.00 0.00 0.00 0.00 1.74 3.22UNK_AI852143 AI852143 112981_at 0.00 0.00 0.00 0.00 3.36 0.00UNK_AW060744 AW060744 112989_at 0.00 0.00 0.00 0.00 2.84 0.00UNK_AA940527 AA940527 113018_at 0.00 0.00 0.00 0.00 2.51 0.00UNK_AA855540 AA855540 113021_at 0.00 0.00 0.00 1.68 1.90 2.98UNK_AI840910 AI840910 113027_at 0.00 0.00 0.00 0.00 2.41 1.83UNK_AA816040 AA816040 113043_at 0.00 1.39 2.10 1.81 1.90 0.00UNK_AI429002 AI429002 113119_at 0.00 0.00 0.00 2.06 0.00 0.00UNK_AI835854 AI835854 113186_at 0.00 0.00 0.00 0.00 1.98 2.98UNK_AI852046 AI852046 113226_at 0.00 0.00 0.00 0.00 1.46 2.36UNK_AW230690 AW230690 113228_at 0.00 0.00 0.00 3.05 0.00 0.00UNK_AW120751 AW120751 113239_at 0.00 0.00 0.00 0.00 2.39 0.00UNK_AW213684 AW213684 113285_at 0.00 0.00 0.00 0.00 5.51 0.00UNK_AI850452 AI850452 113288_at 0.00 0.00 1.97 0.00 1.78 3.18UNK_AA967846 AA967846 113328_at 0.00 0.00 0.00 1.93 1.72 2.18UNK_AW214631 AW214631 113333_at 0.00 0.00 1.64 1.58 1.86 2.27UNK_AA793994 AA793994 113443_r_at 0.00 0.00 0.00 1.85 2.32 0.00UNK_AI429737 AI429737 113541_at 0.00 0.00 0.00 2.43 0.00 0.00UNK_AI843578 AI843578 113548_at 0.00 0.00 0.00 0.00 2.22 1.41UNK_AI844170 AI844170 113550_at 0.00 0.00 0.00 0.00 2.03 0.00UNK_AI846429 AI846429 113574_at 0.00 0.00 0.00 0.00 3.35 0.00UNK_AW049388 AW049388 113620_at 0.00 0.00 0.00 0.00 4.93 0.00UNK_AW047525 AW047525 113629_at 0.00 0.00 0.00 0.00 2.74 0.00UNK_AW047341 AW047341 113656_at 0.00 0.00 0.00 0.00 2.02 0.00UNK_AW050247 AW050247 113657_at 0.00 0.00 0.00 0.00 2.44 0.00UNK_AW048440 AW048440 113695_at 0.00 0.00 0.00 0.00 4.37 0.00UNK_AW120861 AW120861 113728_at 0.00 0.00 0.00 0.00 1.99 2.07UNK_AA915716 AA915716 113777_at 0.00 0.00 1.73 1.61 1.91 3.04UNK_AW048627 AW048627 113863_at 0.00 0.00 0.00 0.00 3.00 0.00UNK_AA014260 AA014260 113896_at 0.00 0.00 0.00 1.74 2.37 0.00UNK_AI425640 AI425640 114001_at 0.00 2.63 0.00 0.00 0.00 0.00UNK_AW211307 AW211307 114102_at 0.00 1.37 0.00 1.47 1.81 2.47UNK_AW061165 AW061165 114140_at 0.00 0.00 0.00 0.00 2.55 0.00UNK_AW214473 AW214473 114168_at 0.00 0.00 0.00 0.00 2.43 0.00UNK_AW121266 AW121266 114323_at 0.00 0.00 0.00 0.00 3.13 0.00UNK_AA756403 AA756403 114379_at 0.00 0.42 2.02 1.46 0.00 0.00UNK_AI050351 AI050351 114461_at 0.00 0.00 1.58 1.62 2.81 0.00UNK_AI874945 AI874945 114525_at 0.00 1.28 0.00 0.00 2.05 1.73UNK_AA290482 AA290482 114667_at 0.00 0.00 0.00 0.00 2.62 1.66UNK_AA399878 AA399878 114695_at 0.00 0.00 2.00 0.00 0.00 0.00UNK_AI842428 AI842428 114698_at 0.00 0.00 0.00 2.51 0.00 0.00UNK_AW120476 AW120476 114709_at 0.00 0.00 0.00 0.00 2.24 0.00UNK_AI847047 AI847047 114718_at 0.00 0.00 0.00 0.00 2.28 0.00UNK_AI267112 AI267112 114747_at 0.00 0.00 0.00 2.24 1.87 0.00UNK_AI851384 AI851384 114830_at 0.00 0.00 0.00 1.59 1.90 2.41UNK_AI847957 AI847957 114880_at 0.00 0.00 2.18 1.92 1.39 1.80UNK_AW123237 AW123237 114955_at 0.00 0.00 0.00 0.00 1.75 2.50UNK_AI314760 AI314760 114996_at 0.00 0.00 0.00 0.00 2.00 0.00UNK_AA967301 AA967301 115032_i_at 0.00 0.00 0.00 1.76 2.89 1.84UNK_AI848847 AI848847 115064_at 0.00 0.00 0.00 0.00 2.36 0.00UNK_AI573356 AI573356 115091_at 0.00 0.00 0.00 3.34 0.00 0.00UNK_AA647787 AA647787 115093_at 0.00 0.00 0.00 0.00 1.90 3.27UNK_AI606104 AI606104 115112_at 0.00 0.00 0.00 0.00 5.07 0.00UNK_AW050362 AW050362 115140_at 0.00 0.00 0.00 0.00 2.84 0.00UNK_AW124719 AW124719 115153_at 0.00 0.00 0.00 0.00 1.70 2.94UNK_AI789647 AI789647 115195_at 0.00 0.00 0.00 1.66 11.32 0.00UNK_AI838694 AI838694 115212_at 0.00 0.00 0.00 2.24 0.00 0.00UNK_AA856478 AA856478 115266_at 0.00 0.00 0.00 0.00 3.97 0.00UNK_AI152744 AI152744 115333_at 0.00 0.00 0.00 1.27 6.94 0.00UNK_AI593245 AI593245 115338_at 0.00 0.00 2.06 0.00 0.00 0.00UNK_AI158964 AI158964 115354_at 0.00 0.00 0.00 0.00 3.71 0.00UNK_AA895031 AA895031 115371_at 0.00 0.00 0.00 0.00 1.99 7.39UNK_AI465535 AI465535 115402_at 0.00 0.00 0.00 0.00 2.68 0.00UNK_AW120513 AW120513 115416_at 0.00 0.00 0.00 0.00 3.28 0.00UNK_AA645547 AA645547 115449_at 0.00 0.00 0.00 0.00 1.77 5.16UNK_AW049627 AW049627 115481_at 0.00 0.00 0.00 0.00 2.75 0.00UNK_AI256692 AI256692 115506_at 0.00 0.00 0.00 0.00 1.60 2.05UNK_AW048699 AW048699 115652_at 0.00 2.11 0.00 1.53 0.00 0.00UNK_AI450439 AI450439 115885_at 0.00 0.00 0.00 0.00 2.93 0.00UNK_AW211469 AW211469 115891_at 0.00 0.00 0.00 0.00 1.97 2.64UNK_AI481691 AI481691 115898_at 0.00 0.00 0.00 0.00 3.98 0.00UNK_AA739008 AA739008 115904_at 0.00 0.00 0.00 0.00 1.82 2.84UNK_AI788994 AI788994 115916_at 0.00 0.00 0.00 0.00 1.32 2.42UNK_AA691429 AA691429 115917_at 0.00 0.00 1.70 1.88 2.26 0.00UNK_AA874421 AA874421 116044_at 0.00 0.00 0.00 1.94 2.10 0.00UNK_AA824110 AA824110 116102_at 0.00 0.00 0.00 0.00 3.55 0.00UNK_AW261562 AW261562 116139_at 0.00 0.00 0.00 0.00 3.24 0.00UNK_AA838903 AA838903 116166_at 0.00 0.00 0.00 0.00 1.95 3.46UNK_AI853928 AI853928 116286_at 0.00 0.00 0.00 2.20 1.92 0.00UNK_AI553581 AI553581 116320_at 0.00 0.00 0.00 0.00 1.60 3.82UNK_AW124054 AW124054 116345_at 0.00 0.00 1.80 1.61 2.25 0.00UNK_AI854429 AI854429 116379_at 0.00 0.00 0.00 0.00 2.14 0.00UNK_AA178683 AA178683 116386_at 0.00 0.00 0.00 0.00 3.10 0.00UNK_AA981888 AA981888 116426_at 0.00 0.00 0.00 0.00 2.50 0.00UNK_AW212535 AW212535 116431_at 0.00 0.00 0.00 0.00 2.17 0.00UNK_AI316839 AI316839 116451_at 0.00 0.00 0.00 0.00 4.73 1.71UNK_AA615200 AA615200 116562_at 0.00 2.64 0.00 0.00 0.00 0.00UNK_AI451360 AI451360 116576_at 0.00 0.00 0.00 0.00 1.76 2.03UNK_AI451563 AI451563 116582_at 0.00 0.00 0.00 0.00 2.90 0.00UNK_AI987726 AI987726 116671_at 0.00 0.00 0.00 0.00 1.75 2.22UNK_AW123023 AW123023 116831_at 0.00 0.00 0.00 0.00 2.29 0.00UNK_AI747220 AI747220 116858_at 0.00 0.00 1.49 1.78 1.76 7.51 MAFBAI849704 116955_at 0.00 0.00 0.00 0.00 2.46 0.00 UNK_AI847605 AI847605116986_at 0.00 0.00 0.00 0.00 2.28 0.00 UNK_AW120935 AW120935 117186_at0.00 1.72 1.60 2.17 1.62 0.00 UNK_AI847496 AI847496 117196_at 0.00 0.000.00 0.00 1.80 4.64 UNK_AI840220 AI840220 117218_at 0.00 0.00 0.00 0.003.04 0.00 UNK_AI848424 AI848424 117235_at 0.00 1.18 0.00 1.34 2.48 0.00UNK_AI843866 AI843866 117260_at 0.00 0.00 0.00 0.00 4.03 0.00UNK_AI841583 AI841583 117276_at 0.00 0.00 0.00 0.00 2.92 0.00UNK_AI849085 AI849085 117310_at 0.00 0.00 0.00 0.00 3.99 0.00UNK_AI835269 AI835269 129180_f_at 0.00 0.00 0.00 0.00 1.87 3.06UNK_AW214234 AW214234 129925_at 0.00 0.00 0.00 0.00 1.88 3.42UNK_AW212719 AW212719 129983_at 0.00 1.93 1.73 3.10 1.52 1.45UNK_AA795716 AA795716 130549_f_at 0.00 6.37 0.00 0.00 0.00 0.00UNK_AU018276 AU018276 130719_at 0.00 0.00 0.00 1.99 1.42 4.14UNK_AW045814 AW045814 130804_at 0.00 0.00 0.00 1.73 2.86 0.00UNK_AU024135 AU024135 132172_at 0.00 0.00 2.03 1.88 0.00 0.00UNK_AI195127 AI195127 132364_i_at 0.00 0.00 0.00 0.00 2.40 0.00UNK_AI594430 AI594430 132365_r_at 0.00 0.00 0.00 0.00 1.89 2.06UNK_AI594430 AI594430 133139_at 0.00 0.00 0.00 3.87 1.76 0.00UNK_AW122295 AW122295 133799_at 0.00 0.00 0.00 0.00 4.06 0.00UNK_AI131700 AI131700 133901_f_at 0.00 0.00 0.00 1.64 0.46 2.10UNK_AI481837 AI481837 134388_at 0.00 1.21 0.00 0.00 1.88 2.31UNK_AI536536 AI536536 134515_at 0.00 0.00 0.00 0.00 1.93 2.29UNK_AI874652 AI874652 134531_at 0.00 0.00 0.00 0.00 4.11 1.62UNK_AW121822 AW121822 134597_at 0.00 0.00 0.00 0.00 4.14 0.00UNK_AI643832 AI643832 134660_at 0.00 0.00 0.00 2.17 1.73 0.00UNK_AA793588 AA793588 134662_f_at 0.00 0.00 0.00 2.20 1.47 1.48UNK_AI585590 AI585590 135172_at 0.00 0.00 0.00 0.00 1.32 2.79UNK_AI480578 AI480578 135314_at 0.00 0.00 1.79 1.78 2.48 2.00UNK_AI842058 AI842058 135355_at 0.00 0.00 0.00 0.00 1.91 3.47UNK_AW228646 AW228646 135552_f_at 0.00 2.62 0.00 0.00 0.00 0.00UNK_AI646499 AI646499 135655_at 0.00 0.00 0.00 2.23 0.00 0.00UNK_AI447921 AI447921 135812_at 0.00 0.00 0.00 0.00 2.23 0.00UNK_AI848262 AI848262 135888_at 0.00 0.00 0.00 1.83 1.89 2.00UNK_AI153331 AI153331 136132_at 0.00 1.92 2.10 1.78 0.00 0.00UNK_AI853191 AI853191 136191_at 0.00 2.22 0.00 0.00 0.00 0.00UNK_AI852455 AI852455 136558_at 0.00 0.00 0.00 0.00 1.01 2.20UNK_AI465462 AI465462 137699_at 0.00 2.23 0.00 0.00 1.35 0.00UNK_AW045500 AW045500 138079_at 0.00 0.00 0.00 0.00 1.62 2.50UNK_AI849673 AI849673 138945_at 0.00 2.27 0.11 0.00 0.00 0.00UNK_AI843433 AI843433 138960_f_at 0.00 0.00 0.00 0.00 1.25 2.04UNK_AI841128 AI841128 140441_at 0.00 2.51 0.00 0.00 0.00 0.00UNK_AW105899 AW105899 140654_at 0.00 0.00 0.00 0.00 1.49 2.03UNK_AA967374 AA967374 140760_at 0.00 0.00 0.00 0.00 2.05 0.00UNK_AI648116 AI648116 140893_at 0.00 0.00 0.00 1.17 2.24 0.00UNK_AW123714 AW123714 140999_at 0.00 1.68 1.97 2.74 1.61 1.53UNK_AA561076 AA561076 141179_at 0.00 2.26 0.00 0.00 0.00 0.00UNK_AI645500 AI645500 97543_at 0.00 0.00 0.00 2.96 1.83 2.01 expressed,D49382 developmentally down-regulated gene 5; Nedd5 96337_at 0.00 0.000.00 0.00 6.05 6.35 PNUTL1 AF033350 98609_at 0.00 0.00 0.00 3.74 5.094.97 MSF AJ250723 98149_s_at 0.00 2.78 2.86 6.13 9.13 4.99 UNK_AW046496AW046496 110272_at 0.00 2.06 5.37 4.90 3.35 3.49 UNK_AA636558 AA63655892459_at 0.00 4.73 9.59 15.62 24.77 14.53 UNK_AB023418 AB023418 97198_at0.00 0.00 0.00 3.04 2.54 4.37 cassette, sub-family X75926 A (ABC1),member 1; Abca1 103035_at 0.00 1.73 2.92 4.20 2.83 4.90 TAP1 U6002098402_at 0.00 0.00 0.00 2.12 2.32 2.07 ACLP7 AI843799 92688_at 0.00 2.012.65 2.91 2.26 2.58 acid phosphatase 2, X57199 lysosomal; Acp2 97904_at0.00 1.93 1.98 3.64 2.94 3.68 UNK_AW123953 AW123953 96573_at 0.00 1.690.00 2.54 1.91 2.14 actin, gamma, M21495 cytoplasmic, actin- like; Actg,Actl 96343_at 0.00 1.72 1.82 3.41 3.64 3.03 UNK_AI836968 AI83696893100_at 0.00 0.00 0.00 3.39 4.40 2.27 vascular smooth X13297 muscle;Actvs 93460_at 0.00 0.00 0.00 0.00 2.49 1.93 activin A receptor, L15436type 1; Acvr1 100751_at 0.00 0.00 0.00 0.00 2.25 2.76 metalloproteaseAF011379 domain (ADAM) 10; Adam10 92414_at 0.00 1.50 0.00 5.97 9.93 8.83a disintegrin and D50411 metalloproteinase domain 12 (meltrin alpha);Adam12 103554_at 0.00 0.00 2.63 3.50 5.47 3.45 a disintegrin andAA726223 metalloproteinase domain 19 (meltrin beta); Adam19 103024_at6.28 10.02 5.98 4.43 4.10 2.38 ADAM8 X13335 103392_at 0.00 0.00 2.423.39 3.92 3.18 adenylate cyclase 7; U12919 Adcy7 94535_at 0.00 0.00 0.000.00 2.19 0.00 ADD1 AW121844 100903_at 0.00 0.00 0.00 2.36 1.77 1.90ADPRT2 AJ007780 99038_at 0.00 0.00 0.00 3.40 4.12 3.85 adenylosuccinateL24554 synthetase 2, non muscle; Adss2 99039_g_at 0.00 1.47 0.00 2.782.26 2.44 adenylosuccinate L24554 synthetase 2, non muscle; Adss2100412_g_at 0.00 0.00 0.00 2.85 2.62 0.00 AEBP1 AF053943 136586_at 0.003.12 3.56 5.26 6.60 6.27 UNK_AA960336 AA960336 96357_at 0.00 1.61 1.852.83 3.78 4.62 AF007010 AW212775 104205_at 0.00 0.00 0.00 3.25 19.164.89 aggrecan, structural L07049 proteoglycan of cartilage; Agc 92210_at0.00 0.00 0.00 0.00 2.69 7.02 Agpt2 AF004326 96025_g_at 0.00 0.00 2.182.51 0.00 0.00 adenosylhomocysteine L32836 hydrolase: Ahcy 103551_at0.00 0.00 0.00 0.00 2.39 4.11 UNK_AW124208 AW124208 116577_at 0.00 0.000.00 0.00 2.86 3.71 UNK_AI450355 AI450355 107536_at 0.00 0.00 2.87 4.473.94 4.08 UNK_AI851964 AI851964 104415_at 0.00 0.00 0.00 0.00 2.85 0.00UNK_AA833293 AA833293 103911_at 0.00 0.00 0.00 0.00 2.57 2.19UNK_AI851573 AI851573 102330_at 2.21 4.90 6.74 9.69 5.41 3.36 AIF1D86382 103443_at 0.00 2.98 0.00 0.00 2.23 0.00 UNK_AA711704 AA71170495148_at 0.00 0.00 1.83 3.07 3.90 5.63 AK2 AB020202 92796_at 0.00 0.004.88 10.36 57.57 19.90 phosphatase 2, liver; J02980 Akp2 96888_at 0.000.00 0.00 2.21 2.04 2.03 UNK_AI839814 AI839814 100970_at 0.00 0.00 0.002.56 2.72 2.86 thymoma viral proto- X65687 oncogene; Akt 98372_at 0.002.97 0.00 5.29 2.86 0.00 UNK_AW050387 AW050387 96243_f_at 0.00 1.81 0.000.00 2.32 3.58 UNK_AW120804 AW120804 102048_at 4.83 7.77 16.74 18.4810.36 4.40 ALRP AF041847 94392_f_at 0.00 2.01 1.70 2.55 2.32 0.00angiogenin; Ang U22516 102054_at 0.00 2.71 0.00 2.96 2.56 2.75 ANKHZNAB011370 93038_f_at 0.00 2.05 2.40 3.64 3.20 3.58 LPC1 M69260 100569_at2.07 2.76 2.79 4.54 4.52 4.67 annexin A2; Anxa2 M14044 101393_at 2.430.00 0.00 2.45 2.13 0.00 ANXA3 AJ001633 100584_at 0.00 0.00 1.67 2.842.85 4.02 annexin A4; Anxa4 U72941 93083_at 0.00 0.00 0.00 2.67 2.692.86 ANXA5 D63423 93587_at 0.00 0.00 0.00 3.45 0.00 0.00 annexin A7;Anxa7 L13129 97529_at 0.00 2.06 0.00 5.97 8.79 7.30 annexin A8; Anxa8AJ002390 102327_at 0.00 0.00 2.07 2.55 3.01 3.11 AOC3 AF078705 103242_at0.00 0.00 0.00 1.94 2.49 2.90 UNK_AW123834 AW123834 103878_at 0.00 0.000.00 2.13 2.21 2.07 AP3B1 AF103809 103796_at 0.00 0.00 0.00 3.99 3.273.46 APAF1 AF064071 102710_at 2.15 2.86 3.37 3.90 3.45 5.22 precursorprotein- AF020313 binding, family B, member 1 interacting protein;Apbb1ip-pending 101035_at 0.00 0.00 2.01 0.00 1.84 2.15 apoptosisinhibitor 5; U35846 Api5 98398_s_at 0.00 2.97 3.11 3.55 2.15 2.64APOBEC1 U22262 95356_at 0.00 1.46 1.78 2.38 2.50 3.08 Apoe D0046693700_at 0.00 0.00 0.00 0.00 2.47 2.59 SIAT9 AI838022 96587_at 0.00 0.000.00 0.00 3.15 2.61 ADP-ribosylation D87900 factor 3; Arf3 92968_at 0.000.00 0.00 0.00 2.14 0.00 ADP-ribosylation D87902 factor 5; Arf5 93097_at0.00 6.15 1.74 1.71 0.00 0.00 Arg1 U51805 101030_at 0.00 0.00 0.00 1.852.12 3.24 homolog B (RhoB); X99963 Arhb 96056_at 0.00 0.00 0.00 3.003.64 4.22 homolog 9 (RhoC); X80638 Arhc 95547_at 0.00 0.00 0.00 0.005.84 3.99 homolog D (RhoD); D89821 Arhd 98001_at 0.00 0.00 2.06 1.832.85 2.92 nucleotide exchange U58203 factor (GEF) 1; Arhgef1 101439_at0.00 0.00 0.00 0.00 2.72 2.07 UNK_AW122716 AW122716 115479_at 0.00 0.002.38 5.55 5.94 3.35 ARP2-PENDING AA792177 95434_at 0.00 2.17 2.13 2.922.24 2.57 UNK_AI851740 AI851740 100931_at 0.00 0.00 0.00 0.00 4.46 4.79arylsulfatase A; As2 X73230 94282_at 0.00 1.86 0.00 3.66 3.84 3.64UNK_AW124297 AW124297 95133_at 0.00 0.00 0.00 0.00 5.31 0.00 asparagineU38940 synthetase; Asns 101984_at 0.00 0.00 0.00 1.79 2.04 2.76 ATX1(antioxidant AF004591 protein 1) homolog 1 (yeast); Atox1 99579_at 0.001.58 0.00 2.44 2.72 3.30 beta 3 polypeptide; U59761 Atp1b3 98126_s_at0.00 0.00 0.00 0.00 2.12 0.00 ATPase, Ca++ X67140 transporting, cardiacmuscle, fast twitch 1; Atp2a1 95746_at 0.00 1.51 0.00 2.69 2.20 7.69ATP6A2 AW123765 95745_g_at 0.00 1.35 0.00 1.80 1.68 6.74 transporting,U13837 lysosomal (vacuolar proton pump), alpha 70 kDa, isoform 2;94301_at 0.00 2.37 2.07 3.22 5.34 8.96 ATP6K AI843269 102854_s_at 0.002.19 0.00 0.00 0.00 0.00 ATPase, Cu++ U03434 transporting, alphapolypeptide; Atp7a 93984_at 0.00 1.88 2.24 3.26 3.23 3.67 Atpi AF00271898960_s_at 0.00 0.00 0.00 1.73 2.48 1.89 UNK_AF029792 AF029792 103002_at0.00 0.00 0.00 1.95 2.15 1.84 B4GALT1 M27923 104005_at 0.00 0.00 0.000.00 5.00 2.43 B4GALT2 AB019541 111981_at 0.00 0.00 0.00 0.00 2.02 0.00BACE2 AW122959 99670_at 0.00 0.00 0.00 0.00 3.45 2.81 Bcl-associateddeath L37296 promoter; Bad 93536_at 0.00 0.00 0.00 3.00 3.22 2.81Bcl2-associated X L22472 protein; Bax 93252_at 0.00 0.00 0.00 0.00 2.570.00 B-cell receptor- X81816 associated protein 31; Bcap31 100026_at0.00 0.00 0.00 5.43 16.18 0.00 BCAT1 U42443 94448_at 0.00 0.00 0.00 2.851.58 2.13 BCL10 AJ006289 102914_s_at 0.00 0.00 0.00 0.00 5.13 13.02BCL2A1B U23778 93869_s_at 0.00 0.00 0.00 2.68 3.36 9.35 BCL2A1D U23781101748_at 0.00 0.00 0.00 0.00 13.92 0.00 bradykinin receptor, U47281beta; Bdkrb 101514_at 0.00 0.00 0.00 2.06 3.68 2.34 BET3-PENDINGAF041433 103647_at 0.00 0.00 3.61 2.66 5.42 16.86 beta-galactosidaseM57734 complex; Bgl 96049_at 0.00 2.06 2.40 4.02 3.69 4.37 BGN X5392898433_at 0.00 2.16 0.00 0.00 1.45 2.01 domain death U75506 agonist; Bid101521_at 0.00 4.32 4.05 5.67 5.14 3.35 API4 AB013819 95803_at 0.00 3.170.00 3.77 3.63 5.29 BIT D85785 95804_g_at 0.00 5.17 0.00 0.00 8.80 10.32BIT D85785 93604_f_at 0.00 0.00 0.00 0.00 2.95 14.19 BL2 AF06126093606_s_at 0.00 0.00 0.00 0.00 3.11 11.25 BL2 AB021966 95557_at 0.000.00 0.00 6.05 10.83 17.24 bone morphogenetic L24755 protein 1; Bmp192701_at 0.00 0.00 0.00 0.00 8.10 7.21 BMP1 AA518586 95012_at 0.00 0.000.00 0.00 1.54 4.40 UNK_AB012808 AB012808 98031_at 0.00 0.00 0.00 0.009.58 0.00 BOKL-PENDING AF027707 94036_at 0.00 0.00 0.00 0.00 5.14 4.93UNK_AI844806 AI844806 93324_at 0.00 0.00 0.00 3.98 3.49 3.40 butyrateresponse M58566 factor 1; Brf1 93104_at 0.00 2.95 2.80 4.02 4.75 5.01BTG1 Z16410 96146_at 0.00 0.00 0.00 3.56 6.34 5.24 BTG3 D83745 104097_at0.00 0.00 1.72 2.12 1.86 0.00 budding uninhibited AF002823 bybenzimidazoles 1 homolog (S. cerevisiae); Bub1 109165_at 0.00 0.00 0.000.00 2.63 0.00 BUB1B AW049504 93042_at 0.00 1.80 0.00 2.82 2.69 3.24benzodiazepine D21207 receptor, peripheral; Bzrp 96718_at 0.00 0.00 0.000.00 1.79 2.12 UNK_AB012727 AB012727 98562_at 0.00 2.80 3.66 5.77 3.764.31 component 1, q X58861 subcomponent, alpha polypeptide; 96020_at0.00 2.88 4.26 6.67 4.45 4.01 component 1, q M22531 subcomponent, betapolypeptide; C1qb 92223_at 0.00 1.85 2.43 4.07 2.93 2.85 component 1, qX66295 subcomponent, c polypeptide; C1qc 103707_at 0.00 2.61 3.37 4.053.10 2.93 C3AR1 U77461 103033_at 0.00 0.00 1.67 2.36 3.44 3.66 C4 X06454101728_at 0.00 2.20 0.00 0.12 3.09 0.00 C5R1 S46665 98483_at 0.00 0.000.00 0.00 5.67 7.91 CACNB3 X94404 95423_at 0.00 2.15 2.96 5.11 3.94 3.37CAI Y00884 100155_at 3.86 2.01 2.63 4.29 1.65 0.00 Cak L57509 101107_at0.00 0.00 0.00 3.14 3.16 2.78 calumenin; Calu U81829 104529_at 0.00 0.001.88 1.93 2.26 2.09 calcium modulating U21960 ligand; Caml 101040_at0.00 1.47 1.28 2.06 1.74 2.07 calpain 2; Capn2 D38117 97942_g_at −1.560.00 0.00 6.16 40.88 8.57 CAPN6 Y12582 97941_at 0.00 0.00 0.00 0.00 8.692.20 CAPN6 Y12582 97943_at 0.00 0.00 0.00 1.98 4.94 2.50 CAPN6 AI74713393499_at 0.00 3.32 1.92 3.16 4.17 4.70 capping protein U16740 alpha 1;Cappa1 102248_f_at 0.00 1.87 0.00 2.83 3.31 2.91 CASK Y17138 102064_at0.00 1.72 0.00 2.05 1.38 2.48 CASP1 L28095 99049_at 0.00 0.00 0.00 0.002.36 3.08 caspase 2; Casp2 D28492 98436_s_at 0.00 0.00 2.32 3.29 4.633.72 apoptosis related U54803 cysteine protease; Casp3 94458_at 0.000.00 0.00 0.00 3.24 3.31 CASP6 Y13087 102328_at 1.67 0.00 3.82 0.00 5.014.40 CASP8 AJ007749 93364_at 0.00 1.84 0.00 2.26 2.32 2.91 CATNA1 X5999098151_s_at 0.00 0.00 0.00 0.00 1.80 3.29 catenin src; Catns Z1780494817_at 0.00 2.19 2.44 4.38 4.24 4.34 CBP1 X60676 93697_at 0.00 0.000.00 0.00 1.72 3.53 CBX4 U63387 99186_at 0.00 8.48 3.62 3.94 5.08 3.50CCNA2 X75483 94294_at 0.00 2.93 3.54 5.89 5.22 5.58 cyclin B2; Ccnb2X66032 94232_at 0.00 2.12 1.47 1.84 2.61 2.72 CCND1 AI849928 99535_at2.08 1.94 0.00 0.00 0.00 0.00 CCR4 AW047630 98153_at 0.00 0.00 0.00 2.041.83 0.00 chaperonin subunit 3 L20509 (gamma); Cct3 98446_s_at 0.00 1.831.75 2.36 1.70 0.00 EPHB4 U06834 98088_at 0.00 0.00 1.54 0.00 2.87 0.00CD14 antigen; Cd14 X13333 103422_at 0.00 0.00 0.00 0.00 2.42 7.86 Cd1d1M63695 101897_g_at 0.00 0.00 0.00 0.00 2.31 5.91 Cd1d2 M63697103005_s_at 2.64 4.50 2.70 3.84 3.12 5.15 CD44 X66084 114697_at 2.654.08 3.95 6.25 8.24 22.18 CD44 AI594062 103089_at 0.00 4.30 5.56 6.225.21 4.03 CD48 antigen; Cd48 X53526 104606_at 2.11 3.68 3.52 4.72 4.147.46 CD52 antigen; Cd52 M55561 94939_at 2.23 3.23 3.49 4.50 3.47 5.59CD53 antigen; Cd53 X97227 103016_s_at 0.00 2.52 3.48 6.07 4.53 15.71CD68 X68273 101878_at 0.00 2.02 3.26 3.66 4.16 3.58 CD72 antigen; Cd72J04170 99584_at 0.00 2.17 0.00 3.40 2.84 2.83 CD82 antigen; Cd82 D14883103040_at 0.00 0.00 0.00 0.00 1.56 2.15 CD83 AI837100 95661_at 0.00 0.000.00 0.00 1.33 2.18 CD9 L08115 102934_s_at 0.00 1.60 0.00 2.80 2.37 0.00CDC25C L16926 100128_at 0.00 8.81 12.87 15.86 16.72 6.21 CDC2A M38724103821_at 0.00 1.77 1.70 1.97 2.01 0.00 CDC6 AJ223087 100006_at 0.000.00 0.00 0.00 6.64 5.01 CDH11 D21253 102852_at 0.00 0.00 0.00 0.00 7.689.75 cadherin 2; Cdh2 M31131 94412_at 0.00 0.00 0.00 0.00 2.88 3.60 CDK2AJ223733 101017_at 0.00 0.00 0.00 0.00 3.17 2.52 CDK4 AA791962 100444_at0.00 0.00 0.00 0.00 3.47 0.00 cyclin-dependent D29678 kinase 5; Cdk594881_at 0.00 0.00 0.00 0.00 3.11 0.00 CDKN1A AW048937 98067_at 0.000.00 0.00 0.00 5.18 0.00 cyclin-dependent U09507 kinase inhibitor 1A(P21); Cdkn1a 95471_at 0.00 −2.68 −2.76 0.00 2.10 1.92 cyclin-dependentU22399 kinase inhibitor 1C (P57); Cdkn1c 101900_at 0.00 0.00 0.00 0.006.10 1.30 CDKN2B AF059567 93094_at 0.00 0.00 0.00 0.00 3.46 3.26degeneration-related U88588 2; Cdr2 109137_at 0.00 0.00 0.00 0.00 3.393.25 CDYL AI157065 100616_at 0.00 0.00 0.00 0.00 2.44 0.00 CENPAAF012710 98770_at 0.00 0.00 0.00 0.00 2.24 0.00 CENPC AF012708107597_f_at 0.00 0.00 4.29 2.70 3.37 0.00 UNK_AA637016 AA63701692788_f_at 0.00 0.00 0.00 2.36 2.67 2.72 CETN3 Y12474 93784_at 0.00 0.000.00 2.99 3.88 2.71 CFDP AB010828 101853_f_at 0.00 0.00 0.00 0.00 3.4211.91 component factor h; M12660 Cfh 92291_f_at 0.00 0.00 0.00 0.00 3.0513.62 related protein; M29008 CFHRB 99119_at 0.00 2.89 3.39 4.99 6.156.26 cofilin 1, non- D00472 muscle; Cfl1 99120_f_at 0.00 0.00 0.00 2.062.24 1.88 cofilin 1, non- R75450 muscle; Cfl1 104509_at 0.00 1.89 0.000.00 2.34 0.00 CH25H-PENDING AF059213 101459_at 0.00 0.00 0.00 0.00 1.602.02 helicase DNA L10410 binding protein 1; Chd1 103088_at 0.00 3.212.88 0.00 0.00 0.00 close homolog of L1; X94310 Chl1 100021_at 0.00 0.002.97 7.77 7.91 0.00 ACRA M17640 96549_at 0.00 0.00 0.00 0.00 3.62 0.00acetylcholine L10076 receptor delta; Acrd 102639_at 0.00 0.00 1.92 2.412.72 2.04 CHTS2 AB011451 92832_at 0.00 0.00 0.00 0.00 4.30 0.00 CISH1U88325 92232_at 6.68 28.29 0.00 13.77 17.42 5.49 cytokine inducibleU88328 SH2-containing protein 3; Cish3 93126_at 0.00 0.00 0.00 0.00 2.5710.46 creatine kinase, X04591 brain; Ckb 97468_at 0.00 6.71 10.12 11.3113.78 6.31 CKS1 AB025409 92762_at 2.53 6.19 4.80 3.95 2.46 3.99 CLECSF6AJ133533 94256_at 0.00 2.07 2.20 3.05 4.36 3.47 CLIC4 AI849533 94254_at0.00 0.00 1.62 2.70 2.24 3.40 CLIC4 AI845237 94255_g_at 0.00 1.55 1.902.51 1.93 3.71 CLIC4 AI845237 103346_at 0.00 0.00 0.00 0.00 2.31 2.73CLK2 AF033564 100579_s_at 0.00 2.13 2.05 2.61 2.89 3.28 polypeptide(Lca); U91848 Clta 95286_at 0.00 1.77 0.00 2.24 0.00 0.00 CLU D14077102794_at 0.00 0.00 1.89 2.10 1.38 1.53 CMKAR4 Z80112 93397_at 2.34 4.183.03 4.05 2.45 3.21 chemokine (C-C) U56819 receptor 2; Cmkbr2 102718_at2.24 3.99 3.37 0.00 2.71 0.00 CMKBR5 AF022990 102719_f_at 1.75 3.77 2.232.28 2.38 1.33 chemokine (C-C) X94151 receptor 5; Cmkbr5 94004_at 0.000.00 0.00 3.43 10.86 9.73 calponin 2; Cnn2 Z19543 100481_at 0.00 0.000.00 0.00 20.07 11.26 procollagen, type XI, D38162 alpha 1; Col11a1103616_at 0.00 0.00 0.00 0.00 25.14 34.25 UNK_AF100956 AF100956 92314_at0.00 0.00 0.00 0.00 10.67 0.00 XII, alpha 1; U25652 Col12a1 102261_f_at0.00 0.00 0.00 0.00 2.65 4.65 COL13A1 U30292 102262_r_at 0.00 0.00 0.000.00 4.29 6.76 COL13A1 U30292 99476_at 0.00 0.00 0.00 1.84 2.80 2.91COL14A1 AJ131395 99637_at 0.00 0.00 0.00 2.41 2.14 2.67 procollagen,type AF011450 XV; Col15a1 99638_at 0.00 0.00 0.00 3.24 5.40 5.62procollagen, type D17546 XV; Col15a1 101881_g_at 0.00 0.00 0.00 4.8110.82 10.32 COL18A1 L22545 102990_at 0.00 2.15 3.36 6.99 10.03 12.96COL3A1 AA655199 98331_at 0.00 0.00 0.00 2.60 3.93 4.38 procollagen, typeIII, X52046 alpha 1; Col3a1 101093_at 0.00 0.00 0.00 2.28 2.02 2.23COL4A1 M15832 101080_at 0.00 1.80 3.49 9.91 19.47 13.93 COL5A1 AB009993101906_at 0.00 2.48 3.11 5.07 3.93 3.93 COL5A2 AA032310 92567_at 0.001.92 2.95 6.03 7.55 9.22 procollagen, type V, L02918 alpha 2; Col5a2113235_at 0.00 0.00 0.00 2.96 1.95 3.12 COL5A3 AA734782 95493_at 0.000.00 0.00 3.72 3.84 3.50 procollagen, type VI, X66405 alpha 1; Col6a193517_at 0.00 0.00 1.99 4.43 6.38 5.80 COL6A2 Z18272 101110_at 0.00 0.002.32 5.51 6.14 5.80 COL6A3 AF064749 100308_at 0.00 2.74 2.14 6.75 37.3514.46 procollagen, type X66976 VIII, alpha 1; Col8a1 104483_at 0.00 0.000.00 0.00 32.61 0.00 COL9A1 L12215 98027_at 0.00 0.00 0.00 0.00 4.610.00 procollagen, type IX, Z22923 alpha 2; Col9a2 102070_at 0.00 0.000.00 0.00 13.24 0.00 UNK_AW212495 AW212495 94305_at 0.00 0.00 0.00 2.820.00 0.00 COLA1 U03419 93340_f_at 0.00 0.00 0.00 4.50 3.30 2.24 COPB2AF043120 93341_r_at 0.00 0.00 0.00 2.46 2.84 1.83 COPB2 AF04312098930_at 0.00 0.00 0.00 0.00 2.06 0.00 UNK_AI844701 AI844701 110860_at0.00 0.00 3.09 3.85 1.24 3.46 COPEB AI846501 94427_at 0.00 0.00 0.002.68 4.76 3.81 COPG1 AI841737 96936_at 0.00 0.00 0.00 2.28 4.10 2.32COPG1 AI020792 95149_at 0.00 0.00 0.00 2.58 1.86 2.06 UNK_AW121088AW121088 104143_at 0.00 0.00 0.00 2.36 3.59 3.04 UNK_AI843212 AI84321296648_at 0.00 13.50 4.26 0.00 5.51 6.88 CORO1A AW122039 98928_at 0.001.68 0.00 3.37 5.06 5.56 CORO1B AW122820 99631_f_at 0.00 1.54 0.00 2.842.08 3.07 COX6A1 U08440 92851_at 0.00 0.00 0.00 0.00 2.49 8.74ceruloplasmin; Cp U49430 95514_at 0.00 0.00 0.00 2.96 4.71 2.89UNK_AI846302 AI846302 93320_at 0.00 1.78 2.64 3.70 2.65 3.94 camitineAF017175 palmitoyltransferase 1, liver; Cpt1a 103492_at 0.00 0.00 0.000.00 10.90 5.75 UNK_AF077738 AF077738 98415_at 0.00 0.00 0.00 0.00 1.352.34 CREME9-PENDING AF046060 98395_at 2.46 1.94 0.00 0.00 0.00 0.00CRHR2 U21729 94061_at 0.00 0.00 0.00 2.64 1.93 2.29 intestinal protein;M13018 Crip 101879_s_at 0.00 0.00 0.00 0.00 1.75 2.34 CRRY M23529103817_at 0.00 2.19 2.37 5.07 8.57 7.80 UNK_AJ006469 AJ006469 92506_at0.00 0.00 0.00 0.00 8.84 0.00 CRTL1 AF098460 101450_at 2.70 2.74 0.000.00 2.07 3.42 factor 1 M21952 (macrophage); Csf1 104354_at 0.00 2.653.08 4.25 2.85 6.88 factor 1 receptor; X06368 Csf1r 99330_at 0.00 2.372.21 3.33 2.11 4.32 factor 2 receptor, M85078 alpha, low-affinity(granulocyte- macrophage); 94284_at 0.00 0.00 0.39 3.31 2.27 2.13UNK_AW122731 AW122731 103210_at 0.00 0.00 0.00 2.89 1.78 2.62 factor 2receptor, M29855 beta 2, low-affinity (granulocyte- macrophage);104248_at 0.00 0.00 0.00 2.35 2.26 2.03 CSNK AW227650 104249_g_at 0.000.00 0.00 1.76 2.15 1.71 CSNK AW227650 100019_at 6.42 11.38 13.27 12.7512.15 9.66 proteoglycan 2; D45889 Cspg2 92608_at 0.00 0.00 2.71 4.255.49 2.97 cysteine rich protein; D88793 Csrp 93550_at 0.00 2.70 4.7012.96 26.37 8.78 cysteine-rich protein D88792 2; Csrp2 100581_at 0.001.94 2.02 3.94 2.84 7.19 cystatin B; Cstb U59807 92554_at 0.00 0.00 0.001.95 2.32 2.05 CTBP2 AF059735 100148_at 0.00 0.00 0.00 0.00 2.25 0.00CCCTC-binding U51037 factor; Ctcf 96912_s_at 0.00 2.20 1.97 3.68 2.784.45 lymphocyte- X15591 associated protein 2 alpha; Ctla2a 103518_at0.00 3.44 3.65 4.74 0.00 0.00 lymphocyte- X15592 associated protein 2beta; Ctla2b 103341_at 0.00 1.78 2.25 2.07 1.92 0.00 triphosphate U49350synthase; Ctps 101019_at 2.09 3.57 4.51 4.05 2.09 2.70 CTSC U74683101020_at 0.00 3.36 5.06 4.28 2.46 3.04 CTSC AI842667 94834_at 0.00 1.762.32 4.76 5.57 5.93 cathepsin H; Ctsh U06119 98543_at 0.00 1.80 2.383.24 2.52 4.10 CTSS AJ223208 92633_at 0.00 1.52 2.44 2.98 2.97 6.50D2WSU143E AJ242663 94054_at 0.00 0.00 0.00 2.97 4.15 3.29 CTTN AI84180894055_at 0.00 0.00 2.52 0.00 5.91 4.16 cortactin; Cttn U03184 97013_f_at0.00 2.71 3.17 4.89 4.48 5.87 CYBA AW046124 100059_at 0.00 2.19 2.493.52 3.30 4.51 alpha polypeptide; M31775 Cyba 100300_at 0.00 0.00 1.712.50 2.50 3.11 beta polypeptide; U43384 Cybb 99979_at 1.51 4.39 2.855.07 6.42 9.91 CYP1B1 X78445 94916_at 0.00 1.59 0.00 2.47 2.67 0.00UNK_AW122260 AW122260 92777_at 0.00 2.49 3.85 4.95 3.04 1.84 cysteinerich protein M32490 61; Cyr61 98619_at 0.00 0.00 0.00 0.00 3.27 0.00UNK_AW121709 AW121709 106255_at 0.00 2.41 2.03 4.64 4.43 4.94UNK_AI840993 AI840993 104358_at 0.00 0.00 0.00 1.86 5.05 0.00UNK_AI853668 AI853668 107526_at 0.00 0.00 0.00 0.00 1.84 2.42UNK_AA710084 AA710084 111683_at 0.00 0.00 0.00 2.21 2.79 4.85 D10UCLA1AA153345 112407_at 0.00 0.00 0.00 0.00 2.20 3.03 D10UCLA1 AI02147097824_at 0.00 1.87 2.19 2.60 2.50 1.64 UNK_AW121031 AW121031 94339_at0.00 0.00 0.00 0.00 2.33 1.99 UNK_AI841330 AI841330 94242_at 0.00 0.000.00 2.16 1.70 1.68 UNK_AA881309 AA881309 93427_at 0.00 0.00 0.00 2.346.05 11.04 UNK_AW122310 AW122310 95480_at 0.00 0.00 0.00 0.00 2.18 0.00D11WSU68E AI847163 107600_at 0.00 0.00 0.00 1.79 2.58 0.00 UNK_AI838753AI838753 111518_at 0.00 0.00 0.00 0.00 2.20 3.30 UNK_AA170647 AA17064793775_at 0.00 0.00 0.00 1.81 1.83 2.23 UNK_AI841894 AI841894 98061_at0.00 0.00 0.00 0.00 3.19 2.83 UNK_AI841192 AI841192 104558_at 0.00 0.000.00 0.00 4.22 3.13 D12WSU95E AA867123 101372_at 0.00 0.00 0.00 2.812.01 0.00 UNK_AI852645 AI852645 98918_at 0.00 0.00 0.00 4.35 5.87 3.22D13WSU115E AI841920 94452_g_at 0.00 0.00 1.63 2.11 2.04 0.00 D13WSU123EAI787627 94450_at 0.00 0.00 1.73 2.44 0.00 0.00 D13WSU123E AI85420294502_at 0.00 1.78 0.00 4.75 3.35 3.47 D13WSU50E AW125724 104419_at 0.001.94 0.00 0.00 2.42 3.99 UNK_AI132380 AI132380 97325_at 0.00 0.00 0.002.68 2.67 2.97 UNK_AA881294 AA881294 94561_at 0.00 0.00 0.00 3.23 4.123.13 UNK_AI836140 AI836140 110414_at 0.00 0.00 0.00 2.05 5.26 3.81UNK_AI594455 AI594455 111499_at 0.00 0.00 0.00 1.56 1.93 2.42UNK_AW046236 AW046236 98013_at 0.00 1.88 2.52 0.00 3.28 3.54UNK_AA666464 AA666464 114305_at 0.00 0.00 0.00 0.00 4.13 5.18UNK_AA739238 AA739238 104633_at 0.00 4.17 3.44 3.82 3.73 2.71 D15WSU122EAW123921 97822_at 0.00 0.00 0.00 0.00 3.38 2.85 UNK_AW122689 AW12268997821_at 0.00 0.00 0.00 2.99 0.00 0.00 UNK_AI646056 AI646056 97823_g_at0.00 0.00 0.00 0.00 1.81 2.08 UNK_AW122689 AW122689 95063_at 0.00 0.000.00 2.11 2.59 1.68 UNK_AI606257 AI606257 95137_at 0.00 3.19 3.65 7.6911.28 4.71 UNK_AI852985 AI852985 97921_at 0.00 0.00 0.00 0.00 2.36 0.00UNK_AI846279 AI846279 110388_at 0.00 0.00 0.00 0.00 2.12 0.00UNK_AW213204 AW213204 115074_at 0.00 2.62 2.33 3.85 12.14 4.46UNK_AI197311 AI197311 111433_at 0.00 0.00 0.00 2.83 5.30 0.00UNK_AA795610 AA795610 109692_at 0.00 0.00 2.28 1.49 0.00 0.00UNK_AI848006 AI848006 104333_at 0.00 6.18 7.27 7.18 9.71 6.35 DNAsegment, Chr U69488 17, human D6S56E5; D17H6S56E-5 96318_at 0.00 0.000.00 3.10 4.21 3.13 D17WSU104E AW045739 134595_at 0.00 0.00 0.00 2.882.15 2.49 UNK_AI006117 AI006117 100154_at 0.00 0.00 0.00 2.77 1.72 2.56D17WSU91E AI836367 104090_at 0.00 0.00 0.00 0.00 2.38 2.01 UNK_AA657164AA657164 96346_at 0.00 −1.46 −2.12 0.00 2.45 5.93 D18UCLA3 AI85402094967_at 0.00 0.00 0.00 0.00 1.66 3.20 UNK_AI851365 AI851365 96838_at0.00 0.00 0.00 0.00 4.46 0.00 RCE1 AI851223 107005_at 0.00 0.00 0.001.90 3.19 0.00 UNK_AI853916 AI853916 113182_at 0.00 0.00 0.00 1.92 2.430.00 UNK_AI844871 AI844871 112787_f_at 0.00 0.00 0.00 2.64 2.54 2.82UNK_AI838572 AI838572 112786_i_at 0.00 0.00 0.00 4.53 3.47 0.00UNK_AI838572 AI838572 103310_at 0.00 0.00 0.00 0.00 2.12 1.91 0 AA220427104740_at 0.00 0.00 0.00 0.00 2.41 2.78 UNK_AW125318 AW125318 95428_at0.00 0.00 2.83 0.00 1.99 0.00 D1WSU40E AA688761 104602_at 0.00 1.59 0.000.00 1.70 3.29 UNK_AW121972 AW121972 104640_f_at 0.00 0.00 0.00 2.442.40 2.19 UNK_AI464596 AI464596 104639_i_at 0.00 0.00 0.00 2.93 2.830.00 UNK_AI464596 AI464596 104225_at 0.00 0.00 0.00 0.00 2.10 2.21UNK_AI645050 AI645050 100054_s_at 0.00 0.00 0.00 0.00 2.09 0.00 ENDOGAW123127 107513_at 0.00 0.00 0.00 2.31 3.11 2.79 UNK_AW123087 AW12308795708_at 0.00 2.11 3.22 5.70 7.02 8.87 UNK_AI843466 AI843466 98016_at0.00 0.00 0.00 2.43 0.00 0.00 D3WSU161E AA981268 95477_at 0.00 0.00 0.000.00 2.08 2.36 UNK_AW125185 AW125185 99621_s_at 0.00 2.08 2.54 2.56 2.882.85 splicing factor AA690583 proline/glutamine rich (polypyrimidinetract-binding protein- associated) (human) 97295_at 0.00 2.47 4.02 4.103.48 2.80 UNK_AW122331 AW122331 104116_at 2.55 2.60 2.64 1.68 0.00 0.00UNK_AW124049 AW124049 107574_at 0.00 0.00 0.00 2.45 2.15 3.00UNK_AI836723 AI836723 98092_at 3.04 3.06 5.10 7.71 4.52 10.69 D5WSU111EAA790307 104176_at 0.00 0.00 0.00 0.00 4.07 3.97 UNK_AI850941 AI85094196675_at 0.00 0.00 0.00 1.94 2.68 2.48 UNK_AW124245 AW124245 104168_at0.00 2.74 2.34 3.99 2.65 3.50 UNK_AA791742 AA791742 94237_at 0.00 2.353.47 5.76 4.82 3.95 D6WSU137E AI846708 95541_at 0.00 2.27 0.00 4.67 5.625.12 D6WSU176E AW125506 104300_at 0.00 1.95 2.90 6.09 4.75 5.14 IQGAP1AI117936 95032_at 0.00 3.40 3.29 6.75 7.34 1.97 PRC1 AA856349 103871_at0.00 0.00 0.00 3.06 3.70 1.44 UNK_AW123729 AW123729 110005_at 0.00 1.940.00 3.25 7.31 5.69 UNK_AA839741 AA839741 103862_r_at 0.00 0.00 0.002.45 2.02 2.13 D7WSU128E AA388099 103861_s_at 0.00 0.00 0.00 2.07 2.290.00 D7WSU128E AA388099 95709_at 0.00 0.00 0.00 3.89 6.25 6.07 D7WSU86EAW012491 106634_at 0.00 0.00 0.00 2.10 0.00 0.00 UNK_AW123293 AW12329396325_at 0.00 0.00 0.00 0.00 1.66 2.12 D8WSU108E AW124874 95430_f_at0.00 1.77 0.00 2.65 2.71 3.32 D9WSU18E AI854154 98045_s_at 2.72 5.833.95 5.13 4.15 3.08 disabled homolog 2 U18869 (Drosophila); Dab298044_at 1.21 2.07 0.00 0.00 1.74 0.00 disabled homolog 2 U18869(Drosophila); Dab2 96008_at 0.00 0.00 0.00 1.99 2.36 0.00 DAD1 U81052117012_g_at 0.00 0.00 0.00 4.00 7.90 3.56 UNK_AW105743 AW105743117011_at 0.00 0.00 0.00 0.00 3.01 0.00 UNK_AW105743 AW105743 103430_at0.00 0.00 0.00 0.00 2.05 0.00 UNK_AW124952 AW124952 95529_at 0.00 1.862.09 5.10 2.54 3.94 drebrin-like; Dbnl U58884 98071_f_at 0.00 2.00 3.673.69 3.07 3.72 deoxycytidine X77731 kinase; Dck 101104_at 0.00 0.00 0.001.46 1.46 2.07 critical region gene AB001990 a; Dcra 96636_at 0.00 1.431.65 2.07 1.84 1.97 UNK_AI852649 AI852649 95682_at 0.00 0.00 0.00 2.052.47 1.54 DDB1 AB026432 95683_g_at 0.00 0.00 0.00 1.88 2.50 1.80 DDB1AB026432 100513_at 0.00 0.00 0.00 1.68 4.36 3.45 DDEF1 AF075461101074_at 0.00 0.00 2.79 4.38 3.63 2.36 phosphooligosaccha D89063ride-protein glycotransferase; Ddost 103598_at 0.00 1.59 0.00 3.29 2.242.18 DDX9 U91922 131478_at 0.00 0.00 0.00 0.00 3.96 3.79 DECR2 AW12065495688_at 0.00 1.75 1.72 2.39 2.05 2.52 spermatocyte Y08460 homolog(Drosophila); Degs 93188_at 0.00 0.00 0.00 4.20 11.48 5.36 DKK3 AJ243964102207_at 0.00 0.00 0.00 0.00 3.35 3.26 UNK_AW123249 AW123249 101975_at0.00 0.00 0.00 0.00 1.62 3.17 DLK1 Z12171 92332_at 0.00 0.00 2.88 0.002.22 0.00 distal-less M80540 homeobox 2; Dlx2 92930_at 0.00 0.00 0.000.00 8.22 7.47 distal-less U67840 homeobox 5; Dlx5 96703_at 0.00 1.793.01 7.33 9.33 5.98 UNK_AB029448 AB029448 103344_at 0.00 0.00 0.00 0.002.04 2.64 DnaJ-like protein 1; L16953 Dnajl1 99184_at 0.00 0.00 0.000.00 1.89 2.60 DNASE2 AW120896 96298_f_at 0.00 1.82 1.92 3.10 3.96 3.65UNK_AF020185 AF020185 103030_at 0.00 0.00 0.00 4.57 7.87 4.91 dynamin;Dnm L31397 103031_g_at 0.00 0.00 0.00 0.00 3.09 3.12 dynamin; Dnm L31397101445_at 0.00 2.65 0.00 0.00 0.00 0.00 DNMT AF036008 113211_at 0.000.00 3.68 4.25 6.78 3.64 DNT-PENDING AW049974 102896_at 0.00 0.00 2.043.64 4.81 3.43 tyrosine kinase 1; U78818 Dok1 102334_at 3.08 3.91 0.000.00 0.00 0.00 DOK2 AF059583 101503_at 3.58 3.12 4.04 8.95 7.81 5.99dihydropyrimidinase- X87817 like 3; Dpysl3 102374_at 0.00 0.00 0.00 0.004.74 4.92 DSCR1L2 AI847661 97341_at 0.00 2.40 3.13 6.07 15.30 4.95DXIMX39E AW124082 96813_f_at 0.00 0.00 1.72 2.21 1.85 2.48 DXIMX46EAI852973 112941_f_at 0.00 1.46 2.93 3.92 4.37 4.97 UNK_AA960514 AA960514112940_i_at 0.00 0.00 0.00 2.74 5.32 7.05 UNK_AA960514 AA960514115503_at 0.00 0.00 0.00 2.37 0.00 0.00 UNK_AI536452 AI536452 93306_at0.00 1.46 0.00 2.07 1.87 1.74 polyposis coli U51196 binding protein Eb1;Eb1 96627_at 0.00 2.70 0.00 4.71 4.42 3.78 Ca2+ antagonist X97755(emopamil) binding protein; Ebp 97411_at 0.00 2.04 3.41 2.85 4.03 1.78ect2 oncogene; Ect2 L11316 92352_at 0.00 0.00 0.00 0.00 2.00 3.30 EDG3AF108021 92867_at 0.00 0.00 0.00 0.00 4.47 3.82 EDR2 AF060076 113230_at0.00 12.60 18.55 27.29 46.06 32.08 UNK_AW210333 AW210333 98407_at 0.000.00 0.00 0.00 4.30 3.00 ephrin B1; Efnb1 U07602 96195_at 0.00 0.00 0.000.00 2.74 5.31 embryonal Fyn- U57686 associated substrate; Efs101842_g_at 0.00 0.00 0.00 0.00 2.82 0.00 EGFR AW049716 115396_at 0.000.00 0.00 0.00 4.40 0.00 UNK_AW212285 AW212285 93058_at 0.00 2.41 2.494.00 4.26 3.39 UNK_AF026481 AF026481 103537_at 0.00 1.28 0.00 0.00 1.952.34 EIF2AK3 AF076681 99101_at 0.00 0.00 0.00 2.72 2.29 0.00 EIF3S7AB012580 92816_r_at 0.00 1.75 1.97 0.00 2.95 2.45 EIF4A1 X03039 93783_at0.00 0.00 0.00 0.00 2.98 0.00 0 M27347 99984_at 0.00 0.00 0.00 0.00 2.332.51 ELK3 L19953 101560_at 2.84 8.50 10.71 11.39 7.26 13.98 EMB AW06133097426_at 0.00 1.52 2.41 2.31 3.42 2.86 EMP1 X98471 93593_f_at 2.04 3.043.13 4.60 5.82 4.88 EMP3 U87948 103507_at 0.00 4.51 20.15 12.03 5.176.40 containing, mucin- X93328 like, hormone receptor-like sequence 1;Emr1 100134_at 0.00 0.00 0.00 4.01 4.92 4.32 endoglin; Eng X77952106642_at 0.00 0.00 1.68 0.00 3.70 1.79 UNK_AW260744 AW260744 104174_at0.00 0.00 0.00 5.50 8.69 10.09 phosphodiesterasel/ J02700 nucleotidepyrophosphatase 1; Pdnp1 115369_at 0.00 0.00 2.74 4.43 7.92 3.04EPB4.1L3 AI835976 96623_at 0.00 2.54 2.75 4.70 5.02 3.50 EPCS21-PENDINGAI853172 103980_at 0.00 0.00 0.00 0.00 4.49 0.00 Epha2 U07634 95298_at0.00 0.00 0.00 0.00 3.47 1.35 Epha3 M68513 93469_at 0.00 0.00 0.00 0.006.34 0.00 EPHB3 Z49086 104482_at 0.00 0.00 0.00 0.00 6.75 0.00epimorphin; Epim D10475 98992_at 0.00 0.00 0.00 2.10 3.71 0.00EPPB9-PENDING AB030483 104006_at 0.00 2.64 0.00 0.00 0.00 0.00 factorreceptor L21768 pathway substrate 15; Eps15 93670_at 0.00 0.00 0.00 4.024.90 3.90 ERF AW048233 94040_at 0.00 1.72 0.00 2.76 2.29 1.74rudimentary D73368 homolog (Drosophila); Erh 98129_at 0.00 1.68 0.004.36 7.07 5.75 UNK_AI852553 AI852553 113283_at 0.00 0.00 2.92 3.42 2.284.63 ESTM25 AI036047 113563_at 0.00 0.00 0.00 0.00 2.14 2.15 ESTM3AI845154 100348_at 0.00 0.00 3.31 0.00 3.48 2.28 ESTM4 AW214136 98025_at1.99 3.06 3.68 5.90 5.31 4.61 integration site 2; M34896 Evi2 98026_g_at0.00 2.64 3.50 4.48 4.34 4.88 integration site 2; M34896 Evi2 94810_at0.00 1.61 0.00 2.32 2.75 2.25 Ewing sarcoma X79233 homolog; Ewsh102811_at 0.00 1.49 2.88 2.92 4.07 10.13 exostoses (multiple) X96639 1;Ext1 141160_f_at 0.00 0.00 0.00 10.92 7.94 16.18 EXT1 AA710704 99929_at0.00 0.00 0.00 0.00 2.47 2.05 EXT2 U72141 99917_at 0.00 0.00 2.33 2.282.10 0.00 enhancer of zeste U52951 homolog 2 (Drosophila); Ezh2 95313_at0.00 0.00 0.00 0.00 2.80 5.33 UNK_AW046032 AW046032 98967_at 0.00 6.617.73 7.50 4.13 2.08 protein 7, brain; U04827 Fabp7 98588_at 0.00 0.000.00 2.92 5.68 4.75 FAH Z11774 92441_at 0.00 0.00 0.00 1.93 5.31 12.02FAP Y10007 96119_s_at 0.00 0.00 0.00 0.00 3.68 4.93 UNK_AA797604AA797604 102114_f_at 0.00 0.00 0.00 0.00 3.74 7.50 UNK_AI326963 AI32696394309_g_at 0.00 0.00 0.00 0.00 1.66 2.46 fibulin 1; Fbln1 X70853101090_at 0.00 1.63 0.00 3.44 2.92 3.24 fibrillin 1; Fbn1 L29454103623_at 0.00 0.00 0.00 −0.04 3.50 0.00 fibrillin 2; Fbn2 L39790130689_at 0.00 1.99 0.00 4.20 3.52 0.00 FBXO17 AI957104 102879_s_at 2.152.81 3.04 3.28 2.15 0.00 Fc receptor, IgG, M31314 high affinity I; Fcgr1101793_at 9.28 18.31 11.96 6.48 1.72 0.00 FCGR1 X70980 102337_s_at 0.006.07 3.61 4.74 4.61 2.61 FCGR2B M31312 97327_at 0.00 2.17 3.19 3.45 1.910.00 specific L26320 endonuclease 1; 92188_s_at 0.00 0.00 0.00 1.71 2.162.22 feline sarcoma X12616 oncogene; Fes 93674_at 0.00 0.00 0.00 2.363.64 0.00 dysplasia homolog; U22325 Fgd1 115755_g_at 0.00 0.00 2.87 3.030.00 0.00 FGD2 AA958624 97509_f_at 0.00 0.00 0.00 0.00 2.00 2.61 FGFR1U22324 93090_at 0.00 2.25 0.00 0.00 15.83 12.11 FGFR2 M23362 93091_s_at0.00 0.00 0.00 0.00 12.79 8.09 factor receptor 2; M63503 Fgfr2 100884_at0.00 8.62 5.24 11.29 12.67 10.44 factor regulated U04204 protein; Fgfrp108539_at 1.30 2.97 3.41 3.92 1.57 0.00 FGFRP2-PENDING AI853558100986_at 0.00 0.00 0.00 1.61 2.26 2.55 FHL2 AF055889 99176_at 0.00 0.000.00 0.00 2.80 2.04 UNK_AI843393 AI843393 97421_at 0.00 3.18 3.75 4.375.50 2.59 factor inducible 16; U42385 Fin16 93294_at 6.49 4.31 6.60 6.529.13 4.84 secreted protein; M70642 Fisp12 103248_at 0.00 0.00 0.00 0.004.54 0.00 FKBP1B AF060872 99546_at 0.00 2.31 0.00 3.07 2.84 2.41 protein2 (13 kDa); M77831 Fkbp2 99082_at 0.00 2.02 2.88 8.30 16.01 13.94protein 6 (65 kDa); L07063 Fkbp6 104746_at 0.00 0.00 0.00 4.08 8.21 6.92FKBP7 AF040252 93731_at 0.00 0.00 0.00 2.75 3.90 3.42 FKBP9 AF09033498441_at 0.00 2.19 2.46 3.50 3.23 2.83 retardation L23971 syndrome 1homolog; Fmr1 104172_at 0.00 1.74 2.18 2.78 1.72 0.00 folate bindingprotein M64817 2; Folbp2 92838_at 0.00 0.00 0.00 0.00 2.65 0.00 FSCN1L33726 98817_at 0.00 2.64 0.00 0.00 4.80 0.00 follistatin; Fst Z29532105369_at 0.00 0.00 2.20 2.45 3.39 3.07 UNK_AW123943 AW123943 94833_at0.00 1.28 0.00 3.60 2.58 3.49 follistatin-like; Fstl M91380 103394_at1.84 3.58 3.01 6.10 4.57 16.04 containing ion U72680 transport regulator5; Fxyd5 100133_at 0.00 0.00 0.00 2.50 2.89 3.88 FYN M27266 93681_at0.00 0.00 0.00 5.25 7.24 0.00 UNK_AW123618 AW123618 97531_at 0.00 0.000.00 15.58 0.00 0.00 G0/G1 switch gene X95280 2; G0s2 97516_at 0.00 2.182.47 4.38 4.79 5.05 alpha glucosidase 2, U92793 alpha neutral subunit;G2an 101294_g_at 0.00 3.52 2.38 0.00 1.94 3.20 G6PD2 Z84471 102292_at2.03 2.13 1.47 0.00 0.00 0.00 DDIT1 U00937 101979_at 2.21 2.10 0.00 2.232.97 0.00 GADD45G AF055638 109336_at 0.00 0.00 0.00 0.00 3.83 0.00GADD45G AI035425 103367_at 0.00 2.04 0.00 0.00 2.18 2.73UDP-N-acetyl-alpha- U18975 D-galactosamine:(N- acetylneuraminyl)-galactosylglucosylceramide- beta-1,4-N- acetylgalactosaminyltransferase; Galgt1 115517_at 0.00 1.62 0.00 0.00 3.39 3.09 GALNSAI845504 94338_g_at 0.00 0.00 0.00 0.00 2.27 0.00 growth arrest M21828specific 2; Gas2 98530_at 0.00 0.00 0.00 0.00 3.47 2.41 GAS5 AI84961598531_g_at 0.00 0.00 0.00 2.10 2.16 1.73 GAS5 AI849615 99067_at 0.001.65 1.75 2.27 2.93 2.61 growth arrest X59846 specific 6; Gas6 100488_at0.00 0.00 0.00 2.15 2.08 2.54 acid beta M24119 glucosidase; Gba103202_at 0.00 0.00 3.29 4.08 1.83 3.84 GBP3 AW047476 114351_at 0.000.00 0.00 1.71 2.75 4.42 GCL AA727943 92655_at 0.00 0.00 0.00 2.20 1.930.00 glucosaminyl (N- U19265 acetyl) transferase 1, core 2; Gcnt1109332_at 0.00 0.00 0.00 1.55 2.61 0.00 UNK_AW046226 AW046226 103590_at0.00 0.00 0.00 2.29 5.83 3.68 UNK_AI507104 AI507104 93575_at 0.00 0.000.00 0.00 2.41 3.91 GGH AF051102 102993_at 0.00 0.00 0.00 3.30 3.20 2.75glycoprotein M85153 galactosyltransferase alpha 1,3; Ggta1 100064_f_at0.00 2.51 1.94 4.11 5.60 7.77 GJA1 M63801 100065_r_at 0.00 2.36 1.963.86 7.28 15.07 GJA1 M63801 104016_at 0.00 2.45 0.00 0.00 0.00 0.00 gapjunction M91236 membrane channel protein beta 5; Gjb5 100395_at 0.000.00 0.00 0.00 2.10 0.00 GLI-Kruppel family X99104 member GLI2; Gli297820_at 0.00 0.00 2.46 3.78 9.89 2.84 GLK AB027012 99141_at 0.00 0.000.00 1.91 1.71 4.95 activator protein; U09816 Gm2a 111347_at 0.00 0.000.00 2.18 2.61 3.02 UNK_AI842321 AI842321 112203_at 0.00 0.00 2.28 0.003.41 3.74 UNK_AI159117 AI159117 97227_at 0.00 0.00 0.00 0.00 2.05 0.00guanine nucleotide M63659 binding protein, alpha 12; Gna12 97195_at 0.000.00 0.00 0.00 1.55 2.31 binding protein, U38501 alpha inhibiting 1;Gnai1 99597_at 0.00 3.19 1.89 3.28 2.96 3.96 GNAI2 AI841629 99596_f_at0.00 1.55 0.00 2.57 2.74 2.78 binding protein, M13963 alpha inhibiting2; Gnai2 99598_g_at 0.00 1.78 1.70 2.78 2.19 2.94 GNAI2 AI84162998403_at 0.00 0.00 0.00 0.00 2.76 0.00 binding protein, X65026 relatedsequence 1; Gna-rs1 94854_g_at 0.00 0.00 1.55 2.04 2.09 2.16 guaninenucleotide U29055 binding protein, beta 1; Gnb1 97458_at 0.00 0.00 0.002.21 2.02 2.23 GNB1 AI845935 94853_at 0.00 0.00 0.00 2.38 1.75 2.56guanine nucleotide U29055 binding protein, beta 1; Gnb1 96911_at 0.001.70 0.00 2.58 2.86 2.20 guanine nucleotide U34960 binding protein, beta2; Gnb2 107026_at 0.00 0.00 1.56 1.38 2.66 2.01 UNK_AW123052 AW12305293949_at 0.00 0.00 0.00 1.26 2.32 1.69 guanine nucleotide M63658 bindingprotein, beta 4; Gnb4 99175_at 0.00 1.95 0.00 3.06 3.53 3.40 GNG10AI843396 100418_at 0.00 0.00 0.00 0.00 2.34 0.00 GNG2 AW123750 104469_at0.00 3.50 3.20 3.84 3.87 3.68 Gp38 M73748 100325_at 2.62 2.49 3.65 4.124.79 5.72 glycoprotein 49 M65027 A, glycoprotein 49 B; Gp49a, Gp49b92217_s_at 2.14 2.62 2.84 3.41 3.42 3.67 Gp49b U05265 100435_at 0.000.00 0.00 0.00 6.50 2.76 GPCR26 U13370 96978_at 0.00 0.00 0.00 0.00 2.312.20 GPH-PENDING AB025258 92611_at 0.00 1.62 2.76 2.64 3.18 2.91 P137U18773 102040_at 0.00 0.00 0.00 0.00 6.38 0.00 GPRK6 Y15798 104257_g_at1.81 3.32 4.39 2.84 3.70 4.44 UNK_AI120844 AI120844 93690_at 0.00 0.000.00 0.00 5.63 2.81 GRB10 AF022072 93691_s_at 0.00 0.00 0.00 1.82 5.282.39 receptor bound U18996 protein 10; Grb10 92263_at 0.00 0.00 0.003.94 7.69 6.29 luecine rich protein, AC002397 B7 gene; Lrpb7 94217_f_at0.00 1.72 0.00 2.30 2.06 1.45 leucine rich protein, AC002397 B7 gene;Lrpb7 103993_at 0.00 0.00 0.00 0.00 4.50 3.02 leucine rich protein,AC002397 B7 gene; Lrpb7 130710_at 0.00 0.00 0.00 0.00 2.21 3.04UNK_AA869432 AA869432 93066_at 0.00 2.00 3.08 4.01 3.19 5.73 GRN D1619595348_at 0.00 3.06 0.00 0.00 0.00 0.00 Gro1 J04596 108045_at 0.00 0.004.00 8.85 37.24 14.80 UNK_AA798520 AA798520 101060_at 0.00 1.98 2.324.79 4.52 3.76 reticulum protein; M73329 Erp 98052_at 0.00 0.00 0.002.10 3.20 2.28 GS15 AF003999 94369_at 0.00 0.00 0.00 0.00 2.95 3.81GSNPAT-PENDING AW123026 94811_s_at 0.00 0.00 0.00 3.37 1.72 0.00 factorIIH, AJ002366 polypeptide 1 (62 kD subunit); Gtf2h1 93588_at 0.00 0.000.00 3.44 3.31 4.17 Gtl3 Z54179 98410_at 0.00 0.00 0.00 2.35 1.93 2.75GTPI AJ007972 98950_at 0.00 0.00 0.00 1.95 1.89 2.29 GTR2 AB017616103038_at 0.00 0.00 0.00 1.95 2.54 2.11 guanylate cyclase L36860activator 1a (retina); Guca1a 97538_at 0.00 2.21 3.31 4.47 4.17 7.37GUS-S M19279 102688_f_at 0.00 0.00 0.00 0.00 17.31 0.00 GZMD X56990102728_f_at 0.00 0.00 0.00 0.00 15.71 0.00 GZME M36901 92866_at 0.002.07 0.00 2.67 2.11 4.52 H2-AA X52643 100998_at 0.00 3.08 0.00 3.81 2.273.97 H2-AB1 M21932 94805_f_at 0.00 2.32 2.24 3.40 2.34 1.33 UNK_M33988M33988 93019_at 0.00 0.00 1.29 2.00 3.96 1.92 HIST5-2AX Z35401 101954_at0.00 0.00 0.00 2.47 2.13 1.72 H2afz U70494 97541_f_at 0.00 0.00 0.002.94 2.21 4.21 D region locus 1; H2-D X00246 97540_f_at 0.00 0.00 0.002.17 1.64 2.90 D region locus 1; H2-D M69069 101886_f_at 0.00 1.56 1.672.67 2.22 3.64 H2-L X52490 98035_g_at 0.00 4.04 0.00 0.00 2.47 9.55H2-DMB1 U35330 98034_at 0.00 1.58 0.00 0.00 2.12 0.00 H2-DMB1 U3533094285_at 0.00 2.10 0.00 2.71 2.02 3.96 class II antigen E X00958 beta;H2-Eb1 97173_f_at 0.00 0.00 0.00 4.33 2.95 7.12 H2-K2 M27134 103371_at0.00 0.00 0.00 2.62 3.44 2.54 UNK_AF100956 AF100956 102161_f_at 0.001.46 0.00 3.22 2.08 4.39 H2-Q2 X58609 98438_f_at 0.00 0.00 0.00 2.741.78 3.55 H2-Q7 X16202 93865_s_at 0.00 0.00 2.00 2.91 2.15 2.95histocompatibility 2, M35244 T region locus 10, histocompatibility 2, Tregion locus 17, histocompatibility 2, T region locus 22,histocompatibility 2, T region locus 9; H2-T10, H2-T17, H2-T22, H2-T998472_at 0.00 0.00 2.30 3.40 2.50 4.96 H2-T23 Y00629 100708_at 0.00 0.000.00 2.88 2.50 2.60 H3 histone, family X13605 3B; H3f3b 111734_at 0.000.00 0.00 3.21 3.18 4.05 UNK_AW121301 AW121301 104125_at 0.00 0.00 0.002.35 1.70 1.64 HA1R-PENDING AA763673 92580_at 0.00 0.00 0.00 2.68 0.000.00 histidyl tRNA U39473 synthetase; Hars 98865_at 0.00 2.65 0.00 3.333.29 0.00 hyaluronan synthase U52524 2; Has2 105550_at 0.00 1.93 2.612.31 2.78 0.00 HAS2 AI122156 103286_at 0.00 0.00 0.00 2.02 3.13 0.00UNK_AB012611 AB012611 93483_at 2.86 5.24 2.12 3.21 10.07 3.83hemopoietic cell J03023 kinase; Hck 99461_at 1.98 5.10 3.27 2.70 2.630.00 hematopoietic cell X84797 specific Lyn substrate 1; Hcls1102851_s_at 0.00 2.75 5.77 5.45 2.90 4.43 HCPH M68902 96046_at 0.00 0.000.00 2.52 1.79 0.00 HDAC1 X98207 92730_at 0.00 0.00 0.00 2.16 0.00 0.00epidermal growth L07264 factor-like growth factor; Hegfl 97334_at 0.001.95 0.00 0.00 4.41 0.00 HES6 AW048812 94840_at 0.00 0.00 0.00 2.49 2.457.00 Hexa U05837 101913_at 0.00 2.34 0.00 3.35 3.35 1.98 HEY1 AW21429898628_f_at 0.00 1.91 0.00 3.83 3.98 3.08 factor 1, alpha AF003695subunit; Hif1a 98629_f_at 0.00 1.97 0.00 3.82 3.68 3.30 HIF1A Y0908593250_r_at 0.00 4.01 0.00 7.33 4.74 4.32 HMG2 X67668 104285_at 0.00 0.000.00 0.00 4.78 0.00 methylglutaryl- M62766 Coenzyme A reductase; Hmgcr96699_at 0.00 1.71 1.85 3.26 3.43 2.91 high mobility group X53476protein 14; Hmg14 101589_at 0.00 2.37 2.80 4.52 3.86 3.35 high mobilitygroup X12944 protein 17; Hmg17 93276_at 0.00 1.63 2.23 2.32 2.69 2.00neurological U90123 expressed sequence 1; Hn1 97272_at 0.00 1.75 2.193.44 4.86 3.11 HNRPA1 M99167 94303_at 0.00 0.57 2.05 0.00 1.69 3.51nuclear U11274 ribonucleoprotein D; Hnrpd 101485_at 0.00 0.00 0.00 5.333.02 2.04 HNRPDL AW124859 93990_at 0.00 0.00 0.00 2.21 1.76 1.61 0Y14196 95232_at 0.00 0.00 0.00 1.94 1.75 2.79 HNRPL AB009392 96092_at0.00 5.71 8.04 13.88 15.44 15.06 haptoglobin; Hp M96827 93351_at 0.000.00 0.00 0.00 4.99 7.54 hydroxyprostaglandin U44389 dehydrogenase 15(NAD); Hpgd 102306_at 0.00 0.00 0.00 3.65 4.58 3.02 HS2ST1 AF060178101962_at 0.00 0.00 0.00 0.00 1.86 2.30 HSC70 AI854884 97261_at 0.001.77 0.00 0.00 2.16 2.28 HSJ2 AF055664 100353_g_at 0.00 2.82 0.00 0.002.79 0.00 HSPA4 AA919208 99816_at 0.00 0.00 0.00 0.00 2.43 0.00 heatshock protein, M20567 70 kDa 2; Hsp70-2 95282_at 0.00 2.04 0.00 2.821.71 1.47 heat shock protein, J04633 86 kDa 1; Hsp86-1 101955_at 0.001.92 1.98 3.00 2.30 1.78 GRP78 AJ002387 96254_at 0.00 1.99 0.00 0.003.44 3.03 HSPF1 AB028272 101399_at 0.00 0.00 0.00 0.00 2.72 0.00perlecan (heparan M77174 sulfate proteoglycan 2); Hspg2 94236_at 0.000.00 0.00 0.00 2.44 1.97 UNK_AI838152 AI838152 100476_at 0.00 0.00 0.000.82 135.39 85.11 IBSP L20232 100050_at 2.63 14.09 11.54 10.70 4.20 6.22inhibitor of DNA M31885 binding 1; Idb1 92614_at 4.55 9.82 5.87 7.789.53 9.08 inhibitor of DNA M60523 binding 3; Idb3 99109_at 0.00 0.000.00 3.13 2.22 1.86 immediate early M59821 response 2; Ier2 94384_at0.00 1.56 0.00 3.55 1.73 2.13 immediate early X67644 response 3; Ier392251_f_at 0.00 1.84 2.88 3.49 2.71 3.51 UNK_AA960657 AA96065794224_s_at 0.00 2.12 3.85 3.55 2.35 2.62 UNK_M74123 M74123 98465_f_at0.00 2.15 4.38 5.23 3.24 3.50 interferon activated M31419 gene 204;Ifi204 104750_at 0.00 3.40 7.66 4.69 2.10 4.67 interferon gamma M63630inducible protein, 47 kDa; Ifi47 100981_at 0.00 0.00 8.75 0.00 3.37 2.08interferon-induced U43084 protein with tetratricopeptide repeats 1;Ifit1 112340_at 0.00 0.00 4.49 1.51 0.00 0.00 UNK_AA178653 AA178653103639_at 0.00 0.00 4.82 7.01 2.67 2.35 interferon-induced U43085protein with tetratricopeptide repeats 2; Ifit2 93956_at 0.00 0.00 4.256.35 0.00 0.00 IFIT3 U43086 100483_at 0.00 0.00 2.24 3.74 4.92 4.19Interferon (alpha and M89641 beta) receptor; Ifnar 101014_at 0.00 0.003.34 0.00 2.93 3.31 IFNAR2 Y09864 101015_s_at 0.00 2.18 1.84 1.70 3.805.13 IFNAR2 AF013486 100552_at 0.00 0.00 0.00 3.89 1.88 2.16 IFNGRM28233 95546_g_at 0.00 0.00 0.00 3.10 6.23 5.82 insulin-like growthX04480 factor 1; Igf1 98623_g_at 0.00 0.00 0.00 0.00 3.20 2.42 IGF2X71922 95082_at 0.00 0.00 0.00 0.00 2.92 4.18 IGFBP3 AI842277 95083_at0.00 0.00 0.00 0.00 7.76 6.72 factor binding X81581 protein 3; Igfbp3101571_g_at 0.00 0.00 0.00 3.58 7.05 8.40 IGFBP4 X76066 103949_at 0.000.00 0.00 0.00 3.03 0.00 Indian hedgehog X76291 homolog, (Drosophila);Ihh 101054_at 0.00 1.83 0.00 2.41 2.02 3.39 Ia-associated X00496invariant chain; Ii 96764_at −2.18 0.00 4.23 4.92 2.47 10.03UNK_AJ007971 AJ007971 111615_at 0.00 0.00 0.00 0.00 3.13 0.00 IKBKBAW209118 99491_at 0.00 2.16 1.76 1.96 3.49 3.19 interleukin 10 U53696receptor, beta; II10rb 99991_at 0.00 2.79 0.00 0.00 1.72 3.32interleukin 17 U31993 receptor; II17r 103486_at 0.63 2.39 2.75 3.67 2.174.47 II1b M15131 93914_at 0.00 4.38 0.00 3.94 3.09 3.44 interleukin 1M20658 receptor, type I; II1r1 93871_at 0.00 0.00 0.00 4.89 1.33 3.75IL1RN L32838 102021_at 3.54 27.39 6.36 13.28 10.97 6.34 interfeukin 4M27960 receptor, alpha; II4ra 102218_at 0.00 2.71 0.00 1.55 0.00 0.00interleukin 6; II6 X54542 101499_at 0.00 0.00 0.00 3.26 2.76 2.65 ILKU94479 100277_at 0.00 0.00 2.28 5.04 4.35 0.00 inhibin beta-A; InhbaX69619 94399_at 0.00 0.00 0.00 0.00 1.14 2.02 INPP5B AI843172 102884_at0.00 2.24 1.00 2.31 1.62 1.57 polyphosphate-5- U51742 phosphatase, 145kDa; Inpp5d 100561_at 0.00 1.75 1.98 2.97 3.51 4.48 IQGAP1 AW20909899103_at 0.00 0.00 0.00 0.00 2.24 0.00 IRF3 AF036341 93425_at 0.00 0.000.00 2.88 0.00 0.00 interferon regulatory AF028725 factor 5; Irf5104669_at 0.00 0.00 1.37 2.31 3.90 2.76 interferon regulatory U73037factor 7; Irf7 98822_at 1.83 2.50 7.89 17.45 7.07 5.85 protein (15 kDa);X56602 Isg15 103634_at 0.00 2.12 0.00 3.40 4.00 3.66 interferondependent U51992 positive acting transcription factor 3 gamma; Isgf3g99010_at 0.00 1.49 0.00 2.51 4.56 3.66 ISLR AB024538 98366_at 0.00 0.000.00 0.00 2.16 3.20 integrin alpha V U14135 (Cd51); Itgav 100124_r_at0.00 0.00 0.00 2.19 1.92 2.34 ITGB1 X15202 102353_at 1.84 2.21 2.43 2.513.29 7.22 ITGB2 M31039 94826_at 0.00 1.64 1.82 2.47 2.59 1.69 ITGB4BPY11460 100601_at 0.00 0.00 0.00 0.00 2.93 0.00 ITGB5 AF022110 103611_at0.00 1.73 0.00 2.11 2.33 2.77 ITGP AB012693 98922_at 0.00 0.00 0.00 0.002.69 2.27 intergral membrane L34260 protein 1; Itm1 93511_at 0.00 0.000.00 0.00 2.04 0.00 integral membrane L38971 protein 2; Itm2 96283_at0.00 0.00 0.00 4.19 9.42 7.02 UNK_AI849180 AI849180 99509_s_at 0.00 0.000.00 0.00 6.28 0.00 JAK3 L40172 103816_at 0.00 0.00 0.00 1.96 1.74 2.64JCAM U89915 102362_l_at 2.25 5.90 2.20 8.24 4.87 0.00 Junb U20735102363_r_at 0.00 6.13 3.53 14.86 4.92 0.00 Junb U20735 102364_at 0.000.00 0.00 0.00 2.24 2.09 JUND1 J04509 114683_at 0.00 0.00 0.00 0.00 2.124.85 KAP AW125126 102892_at 0.00 2.18 0.00 0.00 1.30 1.61 KCNAB2 U65592109931_at 0.00 0.00 0.00 0.00 4.27 2.96 UNK_AW214619 AW214619 102335_at0.00 0.00 0.00 0.00 4.22 5.08 KCNK1 AF033017 104652_at 0.00 0.00 0.000.00 1.71 3.71 KCNK2 AI849601 102198_at 0.00 5.02 4.23 5.49 6.12 6.03KCNN4 AF042487 102644_at 0.00 2.13 2.16 3.29 3.28 4.38 derivedtranscript 1; U13371 Kdt1 106026_at 0.00 0.00 0.00 2.22 1.11 0.00 KELCHLAI845205 99541_at 0.00 0.00 2.42 2.19 2.31 1.50 KIFL1 AJ223293 94276_at0.00 2.50 0.00 2.52 1.93 2.89 UNK_AF064635 AF064635 100010_at 0.00 0.000.00 0.00 2.38 2.04 Kruppel-like factor 3 U36340 (basic); Klf3 99622_at0.00 0.00 0.00 0.00 2.46 2.79 Kruppel-like factor 4 U20344 (gut); Klf4102707_f_at 0.00 0.00 3.80 0.00 0.00 0.00 kallikrein binding X61597protein; KIkbp 93677_at 0.00 0.00 0.00 1.68 2.07 1.74 KLRD1 AF03031192790_at 0.00 3.36 3.06 3.84 3.02 2.72 (importin) alpha 2; D55720 Kpna297991_at 0.00 2.56 0.00 0.00 2.22 0.00 Kirsten rat sarcoma X02452oncogene 2, expressed; Kras2 97909_at 0.00 5.50 6.71 11.66 11.44 8.79UNK_AI838080 AI838080 104587_at 0.00 0.00 0.00 3.06 4.57 4.63 Lama4U69176 101948_at 0.00 0.00 0.00 2.83 5.29 1.96 LAMB1-1 X05212 140322_at0.00 0.00 2.48 2.50 2.39 2.59 LAMP2 AW018326 100136_at 0.00 0.00 0.002.49 2.82 2.87 LAMP2 M32017 100012_at 0.00 2.03 3.10 3.09 4.43 8.86associated protein U29539 transmembrane 5; Laptm5 93793_at 0.00 1.731.73 3.30 4.36 5.96 LASP1 AW122780 93930_at 0.00 0.00 0.00 1.83 4.324.37 LIM and SH3 protein U58882 1; Lasp1 114629_at 0.00 0.68 2.63 3.491.80 2.04 UNK_AW124408 AW124408 102957_at 0.00 3.04 0.00 3.19 2.47 4.63lymphocyte cytosolic U20159 protein 2; Lcp2 93682_at 0.00 0.00 0.00 0.002.02 1.93 LDB3 U89489 93797_g_at 0.00 2.55 1.84 3.48 3.05 2.86 TCFL1AW123952 93798_at 0.00 2.67 0.00 3.36 3.02 3.32 TCFL1 AI839988 93600_at0.00 1.83 2.22 2.93 3.37 4.78 LEPR AJ011565 100431_at 0.00 0.00 0.000.00 4.53 5.21 leptin receptor; Lepr U42467 95706_at 0.00 0.00 1.74 4.153.83 10.29 binding, soluble 3; X16834 Lgals3 103335_at 0.00 1.81 2.082.99 2.89 2.47 binding, soluble 9; U55060 Lgals9 104659_g_at 0.00 0.000.00 0.00 5.33 11.04 LIFR D17444 104657_at 0.00 0.00 0.00 0.00 1.77 3.26leukemia inhibitory D26177 factor receptor; Lifr 102123_at 0.00 0.000.00 3.18 1.67 3.11 UNK_Z31689 Z31689 98059_s_at 0.00 2.68 2.74 4.633.92 2.97 lamin A; Lmna D49733 93666_at 0.00 0.00 0.00 0.00 2.00 0.00LMO2 M64360 95069_at 0.00 0.00 0.00 0.00 3.14 2.18 UNK_AA940430 AA94043098122_at 0.00 0.00 0.00 0.00 2.19 1.94 LMO4 AF074600 93939_at 0.00 0.000.00 0.00 3.16 1.74 LNK U89993 93885_g_at 0.00 0.00 0.00 0.00 1.92 3.59LOC53423 AB034693 94997_at 0.00 0.00 0.00 0.00 1.76 2.65 LOC53423AF060883 101518_at 0.00 0.00 0.00 3.58 5.95 4.14 uterine protein; U38981LOC55978 92569_f_at 0.00 0.00 2.09 2.56 2.98 0.00 LOC55989 AF053232115414_at 0.00 2.55 0.00 2.70 0.00 0.00 UNK_AI849017 AI849017 104524_at0.00 1.64 1.93 0.00 2.21 3.77 UNK_AI842825 AI842825 96260_at 0.00 0.001.44 2.63 2.92 3.01 UNK_AB021491 AB021491 116843_at 0.00 0.00 0.00 0.062.61 2.86 UNK_AW045920 AW045920 93753_at 0.00 1.85 1.80 3.48 2.78 4.85UNK_AI852632 AI852632 109105_i_at 0.00 0.00 0.00 1.57 4.79 4.72UNK_AW122202 AW122202 109106_f_at 0.00 0.00 0.00 2.28 2.86 1.89UNK_AW122202 AW122202 111200_at 0.00 0.00 0.00 0.00 2.70 0.00UNK_AA726446 AA726446 96139_at 0.00 0.00 0.00 0.00 6.31 0.00UNK_AF001797 AF001797 113180_at 0.00 0.00 0.00 0.00 2.75 0.00UNK_AW125855 AW125855 113101_f_at 0.00 0.00 0.00 0.00 2.07 0.00UNK_AI644869 AI644869 113215_i_at 0.00 0.00 0.00 0.00 2.52 1.42UNK_AI850449 AI850449 113231_at 0.00 0.00 0.00 2.09 2.43 2.31UNK_AI854099 AI854099 111385_at 0.00 0.00 0.00 0.00 3.75 0.00UNK_AA734127 AA734127 138455_at 0.00 0.00 0.00 4.25 4.54 7.46UNK_AI847317 AI847317 107403_at 0.00 0.00 0.00 0.00 5.41 2.12UNK_AW047735 AW047735 111239_at 0.00 0.00 0.00 1.67 3.73 1.58UNK_AI428160 AI428160 100408_at 0.00 0.00 0.00 0.00 2.27 0.00UNK_AA839465 AA839465 116332_at 0.00 0.00 0.00 0.00 2.64 0.00UNK_AW228823 AW228823 111391_at 0.00 2.16 0.00 2.12 4.09 3.51UNK_AI846729 AI846729 101073_at 0.00 0.00 0.00 1.86 1.89 2.07 lowdensity X67469 lipoprotein receptor related protein; Lrp 92564_at 0.000.00 0.00 0.00 2.44 1.96 LRRFIP1 AI891475 104093_at 0.00 1.65 0.00 3.087.88 3.15 LSP1 D49691 103571_at 0.00 2.58 2.53 4.71 12.61 7.37 LST1U72644 100540_at 0.00 0.00 0.00 1.94 2.39 2.10 leukotriene A4 M63848hydrolase; Lta4h 103209_at 0.00 0.00 0.00 0.00 2.04 0.00 UNK_AF022889AF022889 92335_at 2.27 5.35 4.42 7.37 8.46 3.49 growth factor betaAF004874 binding protein 2; Ltbp2 96090_g_at 0.00 0.00 0.00 0.00 1.482.59 UNK_AI255972 AI255972 93353_at 0.00 0.00 0.00 2.37 4.25 4.32lumican; Lum AF013262 96065_at 0.00 2.48 2.99 4.79 10.45 4.81 latexin;Lxn D88769 114822_f_at 0.00 0.00 0.00 2.23 1.71 2.53 UNK_AA762251AA762251 100771_at 0.00 2.32 0.00 3.22 2.64 0.00 LY57 AF068182100772_g_at 0.00 0.00 0.00 3.32 3.38 0.00 LY57 AF068182 93078_at 0.000.00 0.00 2.01 0.00 0.00 LY6 X04653 101487_f_at 0.00 1.52 1.77 2.89 2.342.43 LY6E U47737 94425_at 0.00 2.66 1.85 3.26 2.53 2.88 LY86 AB007599100468_g_at 0.00 1.84 2.02 2.66 1.65 2.94 lymphoblastomic X57687leukemia; Lyl1 100467_at 0.00 0.00 2.64 0.00 0.00 0.00 lymphoblastomicX57687 leukemia; Lyl1 103349_at 0.00 2.70 2.60 0.00 4.26 0.00 viral(v-yes-1) M57696 oncogene homolog; Lyn 101753_s_at 0.00 1.77 2.34 3.142.90 3.36 LZP-S X51547 100477_at 0.00 3.23 0.00 7.39 9.49 5.76hypothetical protein M32486 19.5; p19.5 92847_s_at 0.00 1.93 1.57 3.011.89 3.90 M6PR X56831 96865_at 0.00 0.00 1.70 2.61 3.59 3.60 alaninerich protein M60474 kinase C substrate; Macs 99632_at 0.00 3.64 3.715.79 4.99 3.29 MAD2L1 U83902 99024_at 0.00 0.00 0.00 2.37 3.96 3.22 Maxdimerization U32395 protein 4; Mad4 102983_at 0.00 0.00 0.00 2.26 2.672.46 MADH1 U58992 102984_g_at 0.00 0.00 0.00 0.00 2.46 2.38 MADH1 U58992104536_at 0.00 0.00 0.00 2.18 2.08 2.27 MADH2 U60530 104220_at 2.64 2.732.60 2.03 1.86 1.93 MADH6 AF010133 114338_at 0.00 2.06 2.77 3.20 3.214.58 MAFB AI642664 102204_at 0.00 2.04 0.00 1.93 3.78 3.95musculoaponeurotic L36435 fibrosarcoma oncogene family, protein B(avian); Mafb 117143_s_at 0.00 0.00 0.00 2.70 2.61 3.69 MAFB AW213708117144_r_at 0.00 0.00 0.00 0.00 4.02 3.31 MAFB AW213708 105228_at 0.001.54 0.00 1.91 3.85 3.66 MAN1B AI528764 110305_at 0.00 0.00 0.00 0.004.70 3.60 MAN1B AA960561 104628_at 0.00 1.85 0.00 4.09 2.33 3.10mannosidase 2, X61172 alpha 1; Man2a1 99562_at 0.00 2.00 2.50 3.15 3.164.31 MAN2B1 U87240 102195_at 0.00 0.00 2.76 2.19 2.65 3.58 proteinkinase U88984 kinase kinase kinase 4; Map4k4 103416_at 0.00 0.00 0.002.14 1.55 1.98 MAPK6 AI844810 98475_at 0.00 0.00 0.00 3.59 8.68 5.06matrilin 2; Matn2 U69262 102089_at 0.00 0.00 0.00 0.00 11.72 0.00 MATN3Y10521 96835_at 0.00 0.00 0.00 0.00 23.39 8.68 MATN4 AJ010984 99095_at0.00 0.00 0.00 1.82 2.24 2.47 Max protein; Max M63903 96767_at 0.00 1.831.99 3.73 4.04 3.18 MBC2 AF098633 100062_at 0.00 2.91 3.11 3.83 3.442.47 maintenance X62154 deficient (S. cerevisiae); Mcmd 93112_at 0.000.00 1.92 0.00 2.36 0.00 MCMD2 D86725 93041_at 0.00 7.24 7.49 6.58 4.252.16 maintenance D26089 deficient 4 homolog (S. cerevisiae); Mcmd4100156_at 0.00 7.39 9.72 7.89 7.48 2.57 maintenance D26090 deficient 5(S. cerevisiae); Mcmd5 93356_at 0.00 0.00 0.00 0.00 2.28 2.63maintenance D26091 deficient 7 (S. cerevisiae); Mcmd7 99133_at 0.00 2.081.76 3.23 3.10 2.32 monoclonal X14309 antibodies 4F2; Mdu1 103584_at0.00 2.17 2.27 3.29 4.01 4.66 UNK_AW124334 AW124334 92607_at 0.00 0.000.00 4.80 35.79 13.98 MEST AF017994 101095_at 0.00 0.00 0.00 0.00 7.2112.75 associated protein 2; L23769 Mfap2 131248_at 1.92 0.00 0.00 2.864.34 2.62 MFAP5-PENDING AI608002 99518_at 1.91 0.00 0.00 2.66 2.54 1.97MFAP5-PENDING AW121179 92880_at 0.00 0.00 0.00 0.00 2.78 1.95 factor 8protein; M38337 Mfge8 103080_at 0.00 2.28 3.11 3.79 2.29 3.86 IFN-gammaU15635 induced; Mg11 110672_at 0.00 0.00 0.00 2.18 0.00 0.00 MGLAW049068 93866_s_at 0.00 0.00 0.00 0.00 2.01 2.44 matrix gamma- D00613carboxyglutamate (gla) protein; Mgiap 104410_at 0.00 0.00 0.00 3.62 2.312.44 UNK_AW124785 AW124785 99457_at 0.00 4.86 5.97 6.25 6.68 4.02antigen identified by X82786 monoclonal antibody Ki 67; Mki67101069_g_at 0.00 1.70 0.00 0.00 2.03 3.10 MKRN1 AA656621 97203_at 0.004.21 3.45 4.84 7.71 7.84 MLP X61399 92331_at 0.00 0.00 0.00 0.00 5.673.92 endopeptidase; M81591 Mme 98280_at 0.00 0.00 0.00 0.00 1.80 2.98UNK_AB021228 AB021228 112880_at 0.00 0.00 0.00 2.93 7.30 4.28 MMP23AA144420 98833_at 0.00 0.00 0.00 0.00 0.53 2.49 metalloproteinase 3;X66402 Mmp3 99957_at 0.00 0.00 0.00 39.03 26.93 96.46 MMP9 X7279595045_at 0.00 1.45 0.00 3.50 3.07 2.57 UNK_AI844469 AI844469 131220_f_at0.00 0.00 0.00 0.00 2.24 0.00 UNK_AW123699 AW123699 95951_at 0.00 3.672.20 3.26 2.12 1.72 MPCL AF061272 99071_at 0.00 1.53 2.18 3.44 4.43 9.63expressed gene 1; L20315 Mpeg1 94857_at 0.00 0.00 0.00 0.00 2.55 2.53N-methylpurine-DNA U10420 glycosylase; Mpg 97803_at 0.00 2.84 3.15 3.772.11 3.63 membrane protein, U38196 palmitoylated (55 kDa); Mpp1103226_at 3.09 5.30 3.98 3.64 2.84 2.41 mannose receptor, Z11974 C type1; Mrc1 100759_at 0.00 0.00 0.00 0.00 7.71 3.67 mannose receptor, U56734C type 2: Mrc2 96633_s_at 0.00 0.00 0.00 2.25 2.20 2.01 Sid393p; Sid393pAA529583 96632_at 0.00 0.00 0.00 2.23 1.96 1.69 UNK_AB025049 AB02504996120_at 0.00 0.00 0.00 2.06 1.64 1.99 MRJ-PENDING AW124750 98373_at0.00 2.29 3.59 2.69 0.00 0.00 UNK_AI462516 AI462516 93234_at 0.00 0.000.00 0.00 3.55 0.00 MSC AF087035 93602_at 0.00 2.16 0.00 0.00 3.26 2.23UNK_AF074714 AF074714 93573_at 0.00 2.93 2.31 8.18 4.56 10.01 Mt1 V00835101561_at 0.00 2.89 2.70 5.96 4.03 7.42 Mt2 K02236 108780_at 0.00 2.322.52 3.20 4.77 3.11 UNK_AI845395 AI845395 100046_at 0.00 0.00 3.84 6.204.36 3.26 folate J04627 dehydrogenase (NAD+ dependent),methenyltetrahydrofolate 98417_at 2.13 0.00 2.31 2.78 1.96 1.90 MX1M21038 96285_at 0.00 1.55 1.71 3.13 2.84 2.61 MYADM AJ001616 104712_at0.00 2.70 2.99 2.96 4.49 2.41 myelocytomatosis L00039 oncogene; Myc102430_at 0.00 4.68 0.00 4.96 6.64 4.14 differentiation X51397 primaryresponse gene 88; Myd88 106557_at 0.00 0.00 0.00 3.15 5.61 4.03UNK_AI132668 AI132668 100923_at 0.00 0.00 0.00 0.00 1.80 2.22 MYO10AJ249706 98409_at 0.00 0.00 1.41 2.83 7.66 9.17 myosin Ib; Myo1b L0092395506_at 0.00 0.00 0.00 0.00 2.37 0.00 MYO1C U96723 101708_at 0.00 0.000.00 0.00 1.61 2.32 myosin If; Myo1f X97650 98968_at 0.00 1.84 2.19 1.681.71 2.15 myosin Va; Myo5a X57377 94713_at 0.00 0.00 0.00 0.00 2.66 4.15myosin VIIa; Myo7a U81453 114776_at 0.00 0.00 0.00 3.11 8.64 5.61 MYO9BAA739159 102986_at 3.53 3.84 2.32 2.76 2.31 0.00 MYOD1 M18779 103053_at0.00 3.08 0.00 8.00 4.91 0.00 MYOG X15784 94408_at 0.00 0.00 0.00 2.012.30 3.18 Ngfi-A binding U47008 protein 1; Nab1 100962_at 0.00 0.00 1.992.66 3.48 3.63 Ngfi-A binding U47543 protein 2; Nab2 103637_at 0.00 0.000.00 0.00 4.22 4.03 NAGA AJ223966 93373_at 0.00 0.00 0.00 0.00 3.21 6.08alpha-N- U85247 acetylglucosaminidase (Sanfilippo disease IIIB); Naglu98587_at 0.00 1.60 2.17 2.65 2.40 1.80 assembly protein 1- X61449 like1; Nap1I1 101108_at 0.00 4.08 0.00 0.00 0.00 0.00 autoantigenic spermAF034610 protein (histone- binding); Nasp 100153_at 0.00 0.00 1.32 4.104.06 2.79 neural cell adhesion X15052 molecule; Ncam 99633_at 0.00 0.000.00 0.00 2.26 0.00 NCDN-PENDING AB017608 102326_at 0.00 4.13 0.00 0.001.95 2.92 NCF2 AB002664 100144_at 0.00 0.00 0.00 2.36 2.06 0.00nucleolin; Ncl X07699 94047_at 0.00 1.49 0.00 2.17 2.44 3.23UNK_AW122935 AW122935 101059_at 0.00 0.00 0.00 2.49 2.14 0.00 NDN D76440100472_at 0.00 0.00 0.00 3.04 2.49 1.99 NPC derived proline D10727 richprotein 1; Ndpp1 107467_at 0.00 0.00 0.00 2.05 2.13 1.80 UNK_AW047444AW047444 92518_at 0.00 0.00 0.00 0.00 2.48 0.00 NEO1 Y09535 103549_at0.00 0.00 0.00 1.88 2.33 0.00 NES AW061260 115217_at 0.00 0.00 0.00 0.002.02 3.11 NFAT5 AI852272 102209_at 0.00 0.00 3.02 6.06 3.92 12.16 NFATC1AF087434 115215_at 0.00 0.00 0.00 5.96 7.00 13.80 UNK_AA638441 AA63844198427_s_at 0.00 0.00 0.00 2.48 1.83 2.18 NFKB1 M57999 100469_at 0.000.00 0.00 2.00 2.53 3.49 NFYA D78642 93563_s_at 0.00 2.18 3.71 4.33 5.303.48 NID2 AB017202 93318_at 0.00 0.00 3.63 0.00 1.52 0.00 NINJ1 U9151392794_f_at 0.00 0.00 1.84 0.00 2.49 1.46 NME1 M35970 102047_at 0.00 0.000.00 2.17 0.00 0.00 NMT1 AF043326 101473_at 0.00 0.00 0.00 0.00 7.665.81 NNMT U86108 104132_at 0.00 0.00 0.00 2.32 3.69 0.00 NOC4 AW047276106115_at 0.00 0.00 0.00 2.39 2.08 0.00 UNK_AI849335 AI849335 102028_at0.00 0.00 0.00 4.05 2.85 3.43 NORE1 AF053959 100507_at 0.00 0.00 0.002.01 4.45 6.67 nephroblastoma Y09257 overexpressed gene; Nov 114812_at0.00 0.00 0.00 2.08 6.43 3.89 UNK_AA869278 AA869278 99564_at 0.00 3.623.98 4.26 2.21 2.67 NP95 D87908 92626_at 0.00 0.00 0.00 3.12 3.55 2.70differentiation and X67209 control gene 1; Npdc1 101634_at 0.00 0.001.77 2.55 2.14 0.00 Npm1 M33212 102796_at 0.00 3.11 0.00 0.00 0.00 0.00Npm3 U64450 101168_at 0.00 0.00 0.00 2.07 2.52 1.94 neoplastic Z31360progression 1; Npn1 93202_at 0.00 0.00 0.00 0.00 2.18 1.62 5′nucleotidase; Nt5 L12059 96666_at 0.00 0.00 0.00 0.00 4.20 0.00N-terminal Asn U57692 amidase; Ntan1 94528_at 1.73 3.32 1.59 1.72 1.900.00 NUBP1 AI846206 94839_at 0.00 0.00 0.00 2.37 2.60 2.29 nucleobindin;Nucb M96823 102197_at 0.00 0.00 0.00 2.38 3.20 2.50 NUCB2 AJ222586101593_at 0.00 0.00 0.00 0.00 3.55 0.00 UNK_AI851454 AI851454 108579_at0.00 2.97 0.00 2.53 5.55 2.93 NUDT5 AI854177 93046_at 0.00 0.00 0.000.00 3.03 1.95 UNK_AW045233 AW045233 102231_at 0.00 0.00 0.00 0.00 7.533.00 OASIS-PENDING AB017614 107525_at 0.00 2.46 5.90 6.26 4.94 5.61 OASLAW211637 101002_at 0.00 2.02 0.00 2.36 1.89 1.67 decarboxylase AF032128antizyme inhibitor; 99549_at 0.00 −3.17 0.00 0.00 3.34 2.12 osteoglycin;Ogn D31951 93369_at 0.00 0.00 0.00 0.00 9.11 5.81 osteomodulin; OmdAB007848 95712_at 0.00 2.64 0.00 3.22 2.28 1.84 UNK_AW045261 AW04526196093_at 0.00 0.00 0.00 3.36 0.00 0.00 UNK_AI842705 AI842705 117253_at0.00 0.00 0.00 1.90 3.19 0.00 UNK_AI845729 AI845729 100437_g_at 0.000.00 0.00 3.83 0.00 0.00 Orm1 M27008 92593_at 2.42 2.26 4.11 5.43 13.5619.79 osteoblast specific D13664 factor 2; OSF-2 102255_at 0.00 0.000.00 3.29 2.68 3.26 OSMR AB015978 100138_f_at 0.00 1.82 2.20 0.00 2.880.00 similar to human X52102 SYK Interacting protein: p16K 95586_at 0.000.00 3.82 3.90 3.26 1.84 P2RX4 AF089751 96016_at 0.00 2.47 0.00 6.194.91 2.57 P40-8 AW045665 104139_at 0.00 0.00 0.00 1.90 2.21 1.822-oxoglutarate 4- U16162 dioxygenase (proline 4-hydroxylase), alpha 1polypeptide; P4ha1 98983_at 0.00 0.00 0.00 2.64 5.05 2.80 2-oxoglutarate4- U16163 dioxygenase (proline 4-hydroxylase), alpha II polypeptide;P4ha2 100720_at 0.00 1.59 2.28 2.36 3.73 2.53 protein, cytoplasmicX65553 1; Pabpc1 98021_at 0.00 0.00 0.00 0.00 2.39 0.00 0 D1433699023_at 0.00 1.65 0.00 4.28 2.73 0.00 factor U57747 acetylhydrolase,isoform 1b, alpha2 subunit; Pafah1b2 100576_at 0.00 0.00 0.00 1.95 2.292.64 factor U57746 acetylhydrolase, isoform 1b, alpha1 subunit; Pafah1b3114355_at 0.00 0.00 2.27 5.58 4.79 0.00 PANX1 AI847747 93298_at 0.000.00 0.00 0.00 3.57 3.43 phosphoadenosine U34883 5′-phosphosulfatesynthase 1; Papss1 96713_at 0.00 0.00 0.00 0.00 5.09 4.94 PAPSS2AF052453 93615_at 0.00 1.75 0.00 2.33 2.68 2.35 pre B-cell leukemiaAF020200 transcription factor 3; Pbx3 94449_at 0.00 0.00 0.00 0.00 2.503.46 PCDH13 AI854522 102280_at 0.00 0.00 0.00 0.00 1.82 3.45 PCDH7AB006758 102781_at 0.00 0.00 0.00 0.00 2.31 2.76 enhanced U37351expression; PCEE 109761_g_at 0.00 0.00 0.00 2.91 5.10 0.00 UNK_AI848972AI848972 101065_at 0.00 3.07 2.87 3.72 2.58 2.41 PCNA X57800 93349_at0.00 0.00 0.00 3.50 6.60 6.15 proteinase enhancer X57337 protein; Pcolce92192_s_at 0.00 0.00 2.04 3.28 4.63 2.79 PCSK5 D12619 101196_at 0.000.00 0.00 0.00 2.74 3.02 convertase D50060 subtilisin/kexin type 6;Pcsk6 95412_at 0.00 0.00 0.00 2.35 2.36 2.10 programmed cell U49112death 6: Pdcd6 96252_at 0.00 1.55 0.00 2.17 2.00 1.80 PDCD6IP AJ00507393382_at 0.00 0.00 0.00 0.00 2.51 0.00 PDE1B1 AF023343 116964_at 0.000.00 0.00 6.04 14.08 9.38 UNK_AI851805 AI851805 93574_at 0.00 0.00 1.713.31 3.42 4.08 SDF3 AF036164 115553_at 0.00 0.00 2.11 2.15 0.00 0.00UNK_AI841779 AI841779 101451_at 0.00 0.00 0.00 2.15 2.01 3.16 PEG3AF038939 96765_at 0.00 0.00 0.00 2.41 2.67 1.76 PEG3 AW120874 94516_f_at0.00 0.00 0.00 0.00 5.97 3.99 PENK2 M55181 101468_at 2.20 3.94 4.04 4.103.07 1.92 properdin factor, X12905 complement; Pfc 97834_g_at 0.00 2.072.29 3.11 2.38 2.29 UNK_AI853802 AI853802 97833_at 0.00 0.00 0.00 2.772.41 0.00 UNK_AI853802 AI853802 93421_at 0.00 3.19 0.00 3.98 5.66 4.45PFTAIRE protein AF033655 kinase 1; Pftk1 101585_at 0.00 0.00 2.28 2.715.13 6.27 PGRMC-PENDING AF042491 94406_at 0.00 0.00 0.00 0.00 6.01 4.58PHTF AJ242864 93708_at 0.00 0.00 0.00 0.00 2.16 1.78 PIAS3 AF03408092312_at 0.00 0.00 0.00 0.00 3.14 0.00 PIK3C2A U55772 96592_at 0.00 0.001.93 0.00 2.15 2.21 phosphatidylinositol U50413 3-kinase, regulatorysubunit, polypeptide 1 (p85 alpha); Pik3r1 101926_at 0.00 0.00 0.00 0.002.74 0.00 proviral integration L41495 site 2; Pim2 95358_at 0.00 0.000.00 1.63 1.80 2.05 UNK_AI843864 AI843864 100328_s_at 4.40 8.50 5.1712.16 2.38 11.48 PIRA3 U96684 98003_at 0.00 2.48 0.00 3.55 3.42 3.45PIRB AF038149 102696_s_at 0.00 0.00 2.49 0.00 2.01 2.44 UNK_AI747899AI747899 101461_f_at 0.00 0.00 0.00 2.09 2.39 2.19 PJA1 U06944 104531_at0.00 1.31 1.42 1.63 2.40 2.42 protein kinase C, X60304 delta; Pkcd97375_at 0.00 0.00 0.00 0.00 2.90 3.20 disease 1 homolog; U70209 Pkd1100951_at 0.00 0.00 0.00 2.13 3.19 3.22 polycystic kidney AF014010disease 2; Pkd2 99513_at 1.58 5.00 0.00 10.15 10.27 5.24 phospholipaseA2, M72394 group 4; Pla2g4 94147_at 4.28 9.58 8.85 11.13 4.61 4.14activator inhibitor, M33960 type I; Planh1 102663_at 0.00 0.00 0.00 5.528.24 0.00 PLAUR X62700 104580_at 0.00 0.00 0.00 0.00 13.32 9.79UNK_U85711 U85711 100607_at 0.00 0.00 6.30 10.02 22.31 16.77 Pld3AF026124 112083_at 0.00 3.60 4.03 3.29 3.72 4.57 PLEK AA389905 116483_at0.00 2.51 0.00 1.45 1.58 1.45 PLEK AA178053 93099_f_at 0.00 0.00 5.640.00 7.14 0.00 homolog, U01063 (Drosophila); Plk 101350_g_at 0.00 0.000.00 2.69 3.15 0.00 PLK-PS1 U73170 112304_at 0.00 0.00 0.00 2.53 2.403.41 PLOD1 AI854890 114376_at 0.00 0.00 0.00 10.32 19.49 16.29 PLOD2AW259579 95009_at 0.00 0.00 0.00 3.52 2.66 0.00 PLOD3 AW107836108848_g_at 0.00 2.15 2.34 3.50 3.60 3.50 UNK_AW261779 AW261779 93323_at0.00 1.77 1.99 4.35 4.15 3.14 UNK_AB031292 AB031292 94278_at 2.52 5.357.31 6.59 8.70 23.61 plastin 2, L; Pls2 D37837 102839_at 0.00 0.00 0.000.00 2.71 0.00 scrambtase 1; D78354 Plscr1 100927_at 0.00 1.61 2.29 3.883.87 3.35 PLTP U28960 97900_at 0.00 0.00 0.00 2.38 0.00 0.00 PLUNCAI845714 93290_at 0.00 3.58 4.71 4.54 4.00 4.14 PNP U35374 103207_at0.00 0.00 0.00 1.97 2.15 1.44 POLA1 D13543 93940_at 0.00 0.00 0.00 0.002.74 2.18 Pon3 L76193 98508_s_at 0.00 0.00 0.00 2.11 1.67 1.47 PPAP2AD84376 109095_at 0.00 0.00 0.00 0.00 1.61 4.80 PPAP2C AI837099 101055_at0.00 0.00 0.00 1.90 2.19 4.26 beta-galactosidase; J05261 Ppgb 101207_at0.00 1.60 1.73 2.43 2.37 2.22 peptidylprolyl X52803 isomerase A; Ppia94915_at 0.00 2.15 2.53 4.59 5.13 5.64 PPIB X58990 100089_at 0.00 0.000.00 2.99 6.25 8.51 peptidylprolyl M74227 isomerase C; Ppic 97507_at0.00 1.87 3.36 5.70 2.90 4.09 isomerase C- X67809 associated protein;Ppicap 98993_at 0.00 2.04 0.00 3.07 3.11 3.12 protein phosphatase U594182, regulatory subunit B (B56), gamma isoform; Ppp2r5c 95631_at 0.00 1.741.72 2.71 2.96 2.24 UNK_AF088911 AF088911 93495_at 0.00 3.41 3.81 6.3310.88 6.68 Prdx4 U96746 95549_at 0.00 0.00 0.00 0.00 2.83 0.00 PRIM2D13545 100684_at 0.00 0.00 1.65 2.87 2.86 2.56 substrate 80K-H; U92794Prkcsh 102414_i_at 0.00 1.63 1.80 2.44 2.02 1.69 interferon inducibleU28423 double stranded RNA dependent inhibitor; Prkri 102415_r_at 0.000.00 0.00 0.00 2.50 0.00 interferon inducible U28423 double stranded RNAdependent inhibitor; Prkri 104728_at 0.00 2.54 0.00 3.40 4.10 4.80 Pros1L27439 103327_at 3.94 5.14 4.58 8.52 7.86 5.35 paired related X52875homeobox 2; Prrx2

96920_at 0.00 −1.76 0.00 0.00 3.99 3.39 PRSS11 AW125478 104102_at 0.000.00 0.00 0.00 5.09 0.00 UNK_AW047978 AW047978 103433_at 0.00 0.00 0.000.00 2.56 2.17 PSCD3 AI846077 102791_at 0.00 2.23 2.86 4.09 2.59 4.48PSMB8 U22033 100588_at 0.00 0.00 0.00 2.43 1.91 2.49 PSME2 U60329103946_at 0.00 3.04 0.00 5.29 5.18 14.26 threonine U87814 phosphatase-interacting protein 1; 102105_f_at 0.00 0.00 0.00 0.00 3.33 0.00 PTGDSAI840733 103362_at 0.00 1.42 0.00 1.93 3.68 0.00 receptor EP4 D13458subtype; Ptgerep4 104406_at 0.00 0.00 0.00 0.00 3.15 1.63 UNK_AI060798AI060798 104538_at 0.00 0.00 0.00 0.00 8.77 10.57 prostaglandin I2AB001607 (prostacyclin) synthase; Ptgis 104647_at 1.32 4.33 7.11 10.538.79 1.69 prostaglandin- M88242 endoperoxide synthase 2; Ptgs2 98482_at0.00 0.00 0.00 4.76 34.85 20.48 PTHR X78936 93646_at 0.00 1.74 0.00 0.004.58 2.84 PTK9 U82324 100718_at 0.00 2.16 2.29 3.42 3.73 4.16 PtmaX56135 96426_at 0.00 1.32 1.37 1.69 2.19 1.80 PTMB4 U38967 97474_r_at0.00 0.00 0.00 0.00 2.93 1.82 pleiotrophin; Ptn D90225 94929_at 0.002.13 0.00 2.61 2.81 4.92 PTPN1 M97590 98424_at 0.00 0.00 0.00 0.00 3.237.57 PTPN13 D83966 92273_at 1.97 3.65 0.00 3.39 0.00 0.00 PTPN18 U49853101996_at 0.00 1.60 0.00 0.00 2.29 1.61 PTPN2 M80739 100976_at 0.00 2.380.00 3.41 4.06 2.87 protein-tyrosine AF013490 phosphatase; Ptpn9103070_at 0.00 3.60 4.76 6.60 10.28 10.14 PTPNS1 AB018194 100908_at 0.000.00 0.00 2.22 6.03 10.00 phosphatase, M36033 receptor type, A; Ptpra101048_at 0.00 2.63 0.00 4.79 2.56 4.70 phosphatase, M14343 receptortype, C; Ptprc 101298_g_at 0.00 3.11 0.00 0.00 1.43 2.85 PTPRC M2315893896_at 0.00 0.00 0.00 0.00 5.11 6.76 phosphatase, D13903 receptortype, D; Ptprd 100427_at 0.00 2.56 2.33 2.28 1.23 2.61 phosphatase,U37465 receptor type, O; Ptpro 92731_at 3.07 17.44 6.55 6.96 5.75 0.00pentaxin related X83601 gene; Ptx3 96719_l_at 0.00 0.00 0.00 0.00 2.580.00 parvalbumin; Pva X59382 97415_at 0.00 0.00 0.00 0.00 3.23 4.63 RASoncogene M89777 family; Rab3d 103579_at 0.00 1.69 0.00 0.00 1.72 5.55RAS-related C3 X53247 botulinum substrate 2; Rac2 97319_at 0.00 3.343.30 9.39 11.41 5.14 UNK_AF084466 AF084466 96104_at 0.00 0.00 0.00 2.142.20 3.10 RAD23B AI047107 104527_at 0.00 0.00 2.19 2.89 2.79 0.00 RAD51D13803 93676_at 0.00 0.00 0.00 0.00 2.01 0.00 RAD51AP1 U93583102649_s_at 0.00 2.14 0.00 2.23 2.22 1.59 RAET1C D64162 106071_at 0.005.58 0.00 6.56 5.61 3.57 RALY AI852199 103299_at 1.92 0.00 2.97 3.914.13 3.15 UNK_AW123773 AW123773 114344_at 0.00 0.00 0.00 2.22 3.25 3.57UNK_AA882453 AA882453 101254_at 0.00 0.00 0.00 2.17 0.00 0.00 oncogenefamily; L32751 Ran 98573_r_at 0.00 2.30 2.42 3.53 2.49 2.60 RAN bindingprotein X56045 1; Ranbp1 93319_at 0.00 1.64 2.16 2.61 4.49 5.27 RAS p21protein U20238 activator 3; Rasa3 102821_s_at 0.00 0.00 0.00 2.31 0.000.00 RAS-like, family 2, L32752 locus 9; Rasl2-9 102379_at 0.00 3.372.64 3.54 0.00 0.00 UNK_AW049415 AW049415 104476_at 0.00 0.00 0.00 2.962.77 2.03 retinoblastoma-like 1 U27177 (p107); Rbl1 96041_at 0.00 2.152.72 3.76 2.78 2.42 RBM3 AB016424 97254_at 0.00 0.00 0.00 2.49 1.83 0.00UNK_AA690061 AA690061 94972_at 0.00 0.00 0.00 0.00 3.12 0.00UNK_AB026569 AB026569 97847_at 0.00 0.00 0.00 0.00 4.07 0.00 RBMXAJ237847 104716_at 0.00 0.00 0.00 3.52 4.52 2.49 protein 1, cellular;X60367 Rbp1 96047_at 0.00 0.00 0.00 0.00 3.29 3.03 protein 4, plasma;U63146 Rbp4 103804_at 0.00 0.00 0.00 0.00 3.42 2.10 ST15 AB006960102960_at 0.00 0.00 0.00 2.03 2.18 2.31 recombination X96618 activatinggene 1 gene activation; Rga 94378_at 0.00 0.00 0.00 0.00 3.49 0.00protein signaling 16; U94828 Rgs16 94899_at 0.00 0.00 0.00 0.00 2.082.09 protein 3; Rhoip3- U73200 pending 104094_at 0.00 0.00 0.00 0.002.15 0.00 LIM gene; Ril- Y08361 pending 114018_at 0.00 2.49 1.95 4.666.14 0.00 UNK_AI504675 AI504675 97091_at 0.00 0.00 0.00 0.00 3.11 2.05interacting serine- U25995 threonine kinase 1; Ripk1 96038_at 0.00 1.760.00 2.90 2.58 2.66 UNK_AI840339 AI840339 93164_at 0.00 0.00 0.00 0.002.18 2.16 ring finger protein 2; Y12783 Rnf2 93782_at 0.00 1.68 1.843.36 3.67 3.28 RNF4 AI844517 93453_at 0.00 0.00 0.00 0.00 2.62 0.00 rodouter segment M96760 membrane protein 1; Rom1 100711_at 0.00 0.00 0.002.10 1.93 0.00 ribosomal protein U12403 L10A; Rpl10a 92834_at 0.00 2.713.10 4.50 4.86 3.15 ribosomal protein X51528 L13a; Rpl13a 94208_at 0.002.29 3.47 4.81 4.93 2.77 RPL27A AW045202 94209_g_at 0.00 2.19 4.15 3.804.81 2.50 RPL27A AW045202 94207_at 0.00 2.31 2.67 4.56 2.55 0.00 RPL27AAI842377 95418_at 0.00 0.00 0.00 0.00 2.52 0.00 UNK_AI848851 AI848851100734_at 0.00 2.31 2.75 3.97 3.44 4.20 ribosomal protein Y00225 L3;Rpl3 108097_at 0.00 0.00 0.00 0.00 2.70 4.31 UNK_AW121237 AW12123799624_at 0.00 0.00 0.00 2.07 2.20 2.07 UNK_AW125517 AW125517 92325_at0.00 0.00 0.00 0.00 3.50 2.79 RPL7A AI326889 96295_at 0.00 2.06 2.944.52 9.84 5.38 RPMS7 AW122030 94076_i_at 0.00 1.53 1.91 3.06 2.69 2.95ribophorin; Rpn D31717 94077_f_at 0.00 0.00 0.00 2.44 2.46 2.44ribophorin; Rpn D31717 98081_at 0.00 0.00 0.00 2.75 3.10 2.31 RPO1-3AI853173 113001_at 0.00 0.00 0.00 2.04 1.65 0.00 RPS12 AI643492101922_at 0.00 1.67 1.76 4.37 4.88 4.01 RPS8 AW123408 100612_at 0.000.00 2.89 0.00 0.00 0.00 ribonucleotide K02927 reductase M1; Rrm1102001_at 0.00 4.09 4.93 4.37 4.89 2.47 ribonucleotide M14223 reductaseM2; Rrm2 101584_at 0.00 0.00 0.00 0.00 2.07 2.03 Ras suppressor X63039protein 1; Rsu1 92399_at 1.56 5.32 7.63 16.64 13.11 6.52 transcriptionfactor D26532 1; Runx1 92676_at 0.00 1.60 2.51 4.67 13.58 14.15transcription factor D14636 2; Runx2 92539_at 0.00 2.45 2.84 3.90 5.124.18 protein A11 M16465 (calgizzarin); S100a10 98600_at 1.80 2.47 2.934.55 7.43 6.03 binding protein A11; U41341 S100a11 100959_at 0.00 1.560.00 2.63 2.65 2.69 binding protein A13; X99921 S100a13 100960_g_at 0.000.00 0.00 1.80 2.42 2.42 binding protein A13; X99921 S100a13 92770_at0.00 0.00 1.83 2.72 2.37 2.61 protein A6 X66449 (calcyclin); S100a695754_at 0.00 0.00 0.00 0.00 2.08 2.47 UNK_AI838216 AI838216 102712_at−3.84 2.96 4.98 8.61 4.23 0.00 Saa3 X03505 102012_at 0.00 3.45 2.78 6.044.14 5.35 SAPS AB014485 97340_at 0.00 0.00 0.00 0.00 9.89 4.81 SART3AI839599 96657_at 0.00 0.00 2.35 3.95 3.54 3.47 N1-acetyl L10244transferase; Sat 99127_at 0.00 0.00 0.00 2.14 2.18 2.16 ataxia 10homolog X61506 (human); Sca10 95758_at 0.00 0.00 1.71 3.17 5.87 3.76 Adesaturase 2; M26270 Scd2 103244_at 0.00 2.16 1.90 6.42 14.12 8.60 SCGFAB009245 101132_at 0.00 0.00 0.00 0.00 2.13 0.00 voltage-gated, typeL36179 VI, alpha polypeptide; Scn6a 92755_f_at 0.00 0.00 0.00 3.02 0.000.00 secretin; Sct X73580 94140_at 0.48 2.44 −2.79 0.00 0.00 0.00 SCVRM59446 93717_at 2.82 3.56 −0.43 1.69 2.72 −0.33 cytokine A12; U50712Scya12 102736_at 2.71 5.21 6.15 9.01 7.67 2.10 small inducible M19681cytokine A2; Scya2 92849_at 2.26 2.31 0.00 0.00 0.00 0.00 smallinducible M58004 cytokine A6; Scya6 94761_at 3.20 6.30 7.57 6.75 7.080.00 SCYA7 X70058 104388_at 2.37 2.97 2.84 3.61 2.34 5.38 SCYA9 U4951393858_at 0.00 0.00 4.64 3.50 1.42 1.46 cytokine B subfamily M33266(Cys-X-Cys), member 10; Scyb10 96953_at 0.00 3.54 0.00 2.92 2.95 0.00KEC AW120786 98772_at 3.38 5.10 0.00 2.26 0.00 0.00 cytokine B U27267subfamily, member 5; Scyb5 98008_at 0.00 0.00 0.00 0.00 5.32 0.00cytokine subfamily U92565 D, 1; Scyd1 96033_at 0.00 0.00 0.00 0.00 3.393.96 syndecan 1; Sdc1 Z22532 95104_at 0.00 0.00 0.00 0.00 7.78 5.08syndecan 2; Sdc2 U00674 98590_at 0.00 1.50 0.00 0.00 5.17 2.08 syndecan4; Sdc4 D89571 93017_at 0.00 2.05 2.50 2.98 2.03 2.97 SDCBP AF077527110314_at 0.00 0.00 0.00 3.88 0.00 0.00 UNK_AA939505 AA939505 93503_at3.23 2.68 3.83 5.83 5.65 6.03 SDF5 U88567 103421_at 0.00 0.00 0.00 2.752.23 4.03 factor receptor 2; D50464 Sdfr2 102319_at 0.00 0.00 0.00 0.002.38 0.00 SDP8 AF062484 110816_at 0.00 1.86 2.60 3.96 4.31 4.31 SEC22L1AI836222 103953_at 0.00 0.00 0.00 4.26 4.62 2.88 trafficking protein-U91538 like 1 (S. cerevisiae); Sec22l1 93711_at 0.00 0.00 0.00 0.00 2.090.00 SEC23A (S. cerevisiae); D12713 Sec23a 98944_at 0.00 2.50 3.56 6.123.76 3.03 UNK_AI848343 AI848343 97882_at 0.00 2.61 2.86 6.48 9.11 5.92SEC61A AB032902 92870_at 0.00 0.00 0.00 2.77 0.00 0.00 SEL1H AF063095100457_at 0.00 0.00 0.00 2.17 2.21 2.29 selectin, endothelial X84037cell, ligand; Selel 104692_at 0.00 2.30 0.00 0.00 0.00 0.00 SELP M7233294063_at 0.00 0.00 0.00 0.00 4.29 0.00 $$ X85991 immunoglobulin domain(Ig), transmembrane domain (TM) and short cytoplasmic domain,(semaphorin) 4A; 103094_at 0.00 0.00 0.00 0.00 5.61 4.54 SERF1 AI036894102641_at 0.00 7.13 3.23 5.34 3.39 11.03 SFPI1 L03215 97997_at 0.00 4.246.40 9.69 9.18 2.33 secreted frizzled- U88566 related sequence protein1; Sfrp1 104672_at 0.00 0.00 0.00 0.00 12.10 0.00 secreted frizzled-U68058 related sequence protein 3; Sfrp3 95791_s_at 0.00 0.00 0.00 2.662.33 0.00 arginine/serine-rich U14648 10, splicing factor,arginine/serine-rich 2 (SC-35); Sfrs10, Sfrs2 94017_s_at 0.00 0.00 0.002.08 0.00 0.00 SFRS2 X98511 101004_f_at 0.00 2.16 2.00 2.68 2.36 2.18splicing factor, X91656 arginine/serine-rich 3 (SRp20); Sfrs3 101861_at0.00 0.00 0.00 0.00 2.24 2.47 SGCE AF031919 96127_at 0.00 2.31 2.89 3.473.36 6.40 SGPL1 AW048730 93806_at 0.00 2.17 2.28 2.89 3.44 5.41UNK_AI848671 AI848671 92975_at 0.00 2.44 2.15 2.25 2.45 3.07 SH3-domainbinding L14543 protein 2; Sh3bp2 103755_at 0.00 0.00 0.00 2.54 5.91 3.28SH3 domain protein D89677 D19; Sh3d19 93275_at 0.00 0.50 0.00 2.58 5.004.00 SH3 domain protein U58885 2B; Sh3d2b 99158_at 0.00 1.76 1.70 3.102.59 2.16 SH3 domain protein U58888 3; Sh3d3 95456_r_at 0.00 0.00 0.000.00 2.03 1.83 deleted gene 1; U41626 Shfdg1 99042_s_at 0.00 0.00 0.002.57 4.04 6.81 SHOX2 U66918 102752_at 0.00 2.08 2.08 3.26 1.98 2.62 SHYCAF072697 94432_at 0.00 0.00 0.00 0.00 2.68 3.64 UNK_AI117157 AI11715799847_at 0.00 0.00 0.00 0.00 3.29 3.93 Siat4 X73523 95599_at 0.00 0.000.00 0.00 4.82 3.35 sialyltransferase 4c; D28941 Siat4c 94492_at 0.000.00 0.00 2.96 3.59 4.98 UNK_AB025406 AB025406 99655_at 0.00 0.00 0.002.64 2.61 2.30 UNK_AB025405 AB025405 95144_at 0.00 0.00 0.00 2.28 1.751.94 UNK_AB024984 AB024984 97489_at 0.00 0.00 0.00 0.00 2.58 3.90UNK_AI846739 AI846739 93789_s_at 0.00 1.63 0.00 2.55 3.08 3.28 SIN3BAF038848 92450_at 0.00 0.00 0.00 0.00 2.37 2.54 SLC12A4 AF047339104719_at 0.00 2.21 0.00 0.00 3.05 2.14 SLC12A7 AI182203 100491_at 0.000.00 0.00 1.90 2.76 0.00 SLC16A2 AF045692 100943_at 0.00 0.00 0.00 7.007.27 2.37 neutral amino acid U75215 transporter; Slc1a4 103065_at 0.001.93 0.00 4.69 6.26 3.25 20, member 1; M73696 Slc20a1 99112_at 0.00 0.000.00 0.00 1.63 3.71 SLC25A10 AA683883 97473_at 0.00 8.03 4.82 19.2314.32 7.15 SLC25A17 AW124470 97472_at 0.00 0.00 0.00 2.35 2.52 0.00SLC25A17 AJ006341 100618_f_at 0.00 0.00 0.00 5.23 4.78 7.59 25(mitochondrial AA062013 carrier; adenine nucleotide translocator),member 5; Slc25a5 97957_at 0.00 0.00 0.00 0.00 2.19 0.00 SLC27A4AF072759 95733_at 0.00 0.00 0.00 0.00 3.22 3.31 UNK_AI838274 AI83827495571_at 0.00 0.00 0.00 0.00 1.83 2.40 SLC30A4 AF004100 101877_at 0.001.78 1.74 2.74 3.70 3.40 SLC31A1 AI854432 103845_at 0.00 0.00 0.00 2.782.72 0.00 UNK_AI839005 AI839005 93558_at 0.00 0.00 0.00 2.33 3.66 2.36SLC35A2 AB027147 100020_at 0.00 0.00 0.00 0.00 3.18 6.84 solute carrierfamily J04036 4 (anion exchanger), member 2; Slc4a2 103818_at 0.00 3.940.00 0.00 7.66 4.45 SLC7A7 AJ012754 104214_at 0.00 2.48 0.00 0.00 0.000.00 SLC7A8 AW122706 99524_at 0.00 0.00 0.00 2.03 0.00 0.00 solutecarrier family AF004666 8 (sodium/calcium exchanger), member 1; Slc8a1102264_at 2.09 0.00 2.47 2.09 1.99 2.48 SLFN1 AF099972 92472_f_at 2.333.93 4.37 4.87 3.05 3.83 SLFN2 AF099973 92471_i_at 0.00 3.71 3.39 5.908.39 4.15 SLFN2 AF099973 92858_at 0.00 4.23 2.55 6.22 7.43 3.89 SLPIAF002719 99552_at 3.78 17.54 20.88 10.28 11.85 25.49 slug, chickenU79550 homolog; Slugh 96050_at 0.00 0.00 0.00 7.04 4.66 0.00 SMARCB1AJ011740 102062_at 0.00 0.00 4.08 0.00 4.73 3.19 matrix associated,U85614 actin dependent regulator of chromatin, subfamily c, member 1;106277_at 0.00 0.00 0.00 2.18 2.30 3.29 UNK_AW120530 AW120530 96812_at0.00 0.00 0.00 2.57 6.03 2.71 SMOH AF089721 103830_at 0.00 2.85 0.000.00 3.62 1.44 snail homolog, M95604 (Drosophila); Sna 101530_at 0.000.00 0.00 2.32 2.60 1.69 ribonucleoprotein U97079 116 kDa; Snrp116-pending 101506_at 0.00 0.00 0.00 2.55 0.00 0.00 UNK_AW227345 AW227345100577_at 0.00 0.00 2.41 0.00 2.31 2.11 small nuclear M58558ribonucleoprotein D1; Snrpd1 112282_s_at 0.00 3.18 4.02 4.54 4.18 4.52UNK_AI154073 AI154073 112283_at 1.68 2.68 0.00 3.14 7.08 5.94UNK_AA718584 AA718584 94550_at 0.00 2.19 1.41 1.85 1.56 2.92UNK_AW121324 AW121324 94902_at 0.00 1.87 0.00 2.17 2.23 1.87 dismutase3, U38261 extracellular; Sod3 111853_at 0.00 0.00 0.00 1.50 4.58 3.78SOUL-PENDING AA726177 104408_s_at 0.00 0.00 0.00 0.00 2.29 2.61 SRY-boxcontaining L35032 gene 18; Sox18 101430_at 0.00 0.00 0.00 2.09 4.36 6.01SOX4 AW124153 100032_at 0.00 0.00 0.00 2.03 2.18 0.00 transcriptionfactor X60136 1; Sp1 113152_at 0.00 0.00 0.00 1.99 2.66 0.00SPAK-PENDING AI850672 97160_at 0.00 0.00 0.00 3.53 3.24 3.71 cysteinerich X04017 glycoprotein; Sparc 97817_at 0.00 1.94 1.93 3.63 3.06 3.46UNK_AW121136 AW121136 104374_at 0.00 5.69 5.43 8.11 4.63 0.00 serineprotease M64086 inhibitor 2-2; Spi2-2 96060_at 0.00 0.00 0.00 2.21 1.731.92 serine protease U25844 inhibitor 3; Spi3 97487_at 0.00 0.00 0.000.00 2.61 6.46 serine protease X70296 inhibitor 4; Spi4 98405_at 0.000.00 0.00 0.00 5.15 0.00 serine protease U96700 inhibitor 6; Spi6102125_f_at 0.00 0.00 1.30 0.00 2.11 0.00 SPI6 AI838923 99528_at 0.000.00 0.00 0.00 1.58 2.19 SPIN AW122015 99563_at 0.00 0.00 0.00 0.00 1.952.49 SPIN AW124681 97519_at 2.00 2.60 5.99 14.15 24.33 29.32 SPP1 X1398694322_at 0.00 2.38 2.44 0.00 3.97 0.56 squalene epoxidase; D42048 Sqle100095_at 0.00 0.00 0.00 1.76 1.71 2.24 scavenger receptor U37799 classB1; Srb1 96712_at 0.00 0.00 0.00 5.45 0.00 0.00 UNK_AI848508 AI84850892540_f_at 0.00 2.10 2.30 7.95 5.95 3.58 SRM Z67748 103568_at 0.00 2.434.42 4.07 17.64 6.56 SRPX-PENDING AB028049 92265_f_at 0.00 0.00 0.000.00 1.91 3.63 SSA2 AF042139 99610_at 0.00 0.00 0.00 0.00 1.96 2.34synovial sarcoma, X93357 translocated to X chromosome; Ssxt 101465_at0.00 0.00 0.00 3.32 2.28 4.66 signal transducer U06924 and activator oftranscription 1; Stat1 115806_at 0.00 0.00 3.13 2.81 0.00 0.00UNK_AI851966 AI851966 99100_at 0.00 0.00 0.00 0.00 2.73 0.00 STAT3AI837104 94331_at 0.00 2.04 0.00 0.00 2.15 2.15 signal transducer L47650and activator of transcription 6; Stat6 93272_at 0.00 0.00 0.00 0.002.30 2.62 STK16 AF062076 98996_at 0.00 2.59 2.69 3.64 4.59 2.59 STK18L29480 92639_at 0.00 1.93 0.00 2.47 2.35 0.00 serine/threonine U80932kinase 6; Stk6 96076_at 0.00 0.00 0.00 2.18 3.12 2.49 UNK_AW121716AW121716 99146_at 0.00 0.00 0.00 1.89 3.17 3.15 UNK_AW124355 AW12435597983_s_at 0.00 0.00 0.00 0.00 2.13 0.00 syntaxin binding D45903 protein1; Stxbp1 95703_at 0.00 0.00 0.00 3.28 1.98 1.70 UNK_AB024303 AB024303101901_at 0.00 0.00 2.31 2.55 1.48 1.72 SUPL15H AB024713 96542_at 0.000.00 0.00 0.00 4.43 4.05 surfeit gene 4; Surf4 M62606 97238_at 0.00 1.752.05 1.79 1.87 0.00 TACC3 AW209238 93541_at 0.00 0.00 0.00 2.16 3.730.00 TAGLN Z68618 93333_at 0.00 0.00 2.00 2.33 2.00 2.02 Tbca U0533398937_at 0.00 0.00 1.55 3.06 3.36 2.94 TBRG1 AW049795 104655_at 0.000.00 0.00 0.00 1.42 2.13 UNK_AA755817 AA755817 97994_at 0.00 0.00 0.000.00 8.61 7.06 TCF7 AI019193 97995_at 0.00 0.00 0.00 0.00 2.94 2.18 7,T-cell specific; X61385 Tcf7 97901_at 0.00 0.00 0.00 0.00 3.66 0.00transcription factor X60831 UBF; Tcfubf 93736_at 0.00 0.00 0.00 0.001.97 3.23 TCN2 AF090686 101540_at 0.00 0.00 0.00 1.89 2.12 1.40 TDGAF069519 108581_at 0.00 0.00 0.00 0.00 2.46 4.50 UNK_AI835817 AI835817116324_g_at 0.00 0.00 0.00 0.00 1.48 2.45 TEDP2-PENDING AI85189393367_at 0.00 0.00 0.00 2.20 3.14 3.08 associated protein 1; U86137 Tep1103385_at 0.00 0.00 0.00 1.97 2.16 1.87 teratocarcinoma U64033expressed, serine rich; Tera 99138_at 0.00 2.50 0.00 2.37 2.41 2.06 TFGAA756292 98514_at 0.00 0.00 0.00 3.17 4.49 2.87 TFPI AF004833 94383_at0.00 0.00 0.00 4.72 5.97 5.52 pathway inhibitor 2; D50586 Tfpi2101918_at 0.00 0.00 0.00 0.00 11.46 8.03 TGFB1 AJ009862 98019_at 0.000.00 0.00 0.00 8.41 3.84 factor beta 1 L22482 induced transcript 1;Tgfb1i1 93728_at 0.00 2.12 2.20 3.09 3.15 2.65 factor beta 1 X62940induced transcript 4; Tgfb1i4 93300_at 0.00 0.00 0.00 0.00 3.26 0.00transforming growth X57413 factor, beta 2; Tgfb2 102751_at 0.00 0.000.00 3.15 3.21 1.80 transforming growth M32745 factor, beta 3; Tgfb392877_at 2.66 4.57 4.66 7.44 3.85 2.47 transforming growth L19932factor, beta induced, 68 kDa; Tgfbi 101502_at 0.00 0.00 2.62 4.72 4.013.84 TG interacting X89749 factor Tgif 104601_at 0.00 2.79 0.00 0.002.21 0.00 Thbd X14432 94930_at 0.00 0.00 0.00 6.81 11.52 6.37 Thbs2L07803 103869_at 0.00 0.00 4.33 17.37 14.36 8.82 protein, mucin 1,U16175 transmembrane, thrombospondin 3; LOC54129, Muc1, Thbs3 99057_at0.00 1.45 0.00 2.57 3.87 1.98 THY1 M12379 93071_at 0.00 0.00 0.00 2.372.57 1.98 TIF1B X99644 93507_at 0.00 0.00 0.00 0.00 3.00 3.30 tissueinhibitor of X62622 metalloproteinase 2; Timp2 103671_at 0.00 0.00 0.000.00 3.68 2.01 TIP30-PENDING AF061972 102273_at 0.00 0.00 0.00 1.73 2.461.93 TJ6 M31226 99935_at 0.00 0.00 0.00 0.00 2.21 2.70 tight junctionprotein D14340 1; Tjp1 96081_at 0.00 0.00 0.67 0.00 8.09 0.00 TK1 X60980110423_at 0.00 0.00 0.00 0.00 6.50 2.22 UNK_AA895554 AA895554 104623_at0.00 0.00 0.00 0.00 2.35 3.25 enhancer of split 3, X73360 homolog ofDrosophila E(spl); 98304_at 0.00 1.55 0.00 2.11 1.46 1.57 TLR6 AB02080892555_at 0.00 0.00 2.39 3.84 11.52 5.85 UNK_AF053454 AF053454 100039_at0.00 0.00 0.00 2.65 5.36 3.33 UNK_AW125880 AW125880 115179_at 0.00 2.540.00 0.00 0.00 0.00 UNK_AA718842 AA718842 99013_f_at 0.00 1.67 0.00 2.363.05 3.11 TMOD3 AI846797 115913_at 0.00 0.00 0.00 2.69 4.01 3.29 TMOD3AI526875 101993_at 0.00 3.87 7.79 16.34 19.51 19.59 tenascin C; TncX56304 98474_r_at 0.00 1.62 2.24 1.98 1.85 2.10 factor induced U83903protein 6; Tnfip6 102887_at 0.00 0.00 0.00 0.00 10.64 3.70 OPG U9433192793_at 0.00 3.30 0.00 2.34 3.22 2.94 TNFRSF1A X57796 94928_at 0.001.58 2.10 2.39 1.72 3.94 TNFRSF1B X87128 93416_at 0.00 1.93 1.50 0.002.12 4.02 factor (ligand) AF019048 superfamily, member 11; Tnfsf11100593_at 0.00 0.00 0.00 0.00 12.73 3.78 TNNT2 L47600 99578_at 0.00 1.983.26 3.07 3.45 1.98 TOP2A U01915 95505_at 0.00 0.00 0.00 2.60 0.00 0.00TOR1B AW060509 97557_at 0.00 0.00 0.00 0.00 3.90 0.00 TOR2A AI84145795345_at 0.00 0.00 0.00 1.80 3.25 2.14 TPBG AJ012160 103032_at 0.00 0.000.00 0.00 2.37 2.26 TPST1 AF038008 94948_at 0.00 0.00 0.00 0.00 4.954.19 TRIP6 AF097511 104154_at 0.00 2.21 0.00 0.00 4.07 0.00 TRP53AB021961 104275_g_at 0.00 0.00 0.00 0.00 2.73 0.00 TRP53 AB02196196183_at 0.00 0.00 2.23 0.00 2.20 2.47 UNK_AW122985 AW122985 93538_at0.00 0.00 0.00 2.02 0.00 0.00 TTRAP-PENDING AW228036 100342_i_at 0.002.12 2.24 4.45 5.18 2.86 TUBA1 M28729 100343_f_at 0.00 1.98 2.03 3.132.91 2.34 TUBA1 M28729 98759_f_at 0.00 2.05 1.98 3.16 3.39 2.73 TUBA2M28727 101543_f_at 0.00 2.06 2.24 3.40 3.14 2.65 TUBA6 M13441 94835_f_at0.00 2.92 2.73 4.98 5.58 3.49 Tubb2 M28739 94788_f_at 0.00 3.11 3.625.63 6.28 4.29 Tubb5 X04663 94789_r_at 0.00 7.98 8.12 78.06 13.75 7.31Tubb5 X04663 98028_at 0.00 0.00 1.73 1.28 5.13 7.55 TWIST M6364992807_at 0.00 1.60 2.05 2.73 2.29 2.42 TXN X77585 93237_s_at 0.00 1.820.00 0.00 4.28 3.89 TYMS AU044050 100397_at 2.04 3.39 3.70 5.63 5.0012.41 TYROBP AF024637 97304_at 0.00 0.00 0.00 0.00 2.07 2.44 UBP1AI836100 98972_at 0.00 0.00 0.00 0.00 5.36 2.56 UNK_AI574262 AI57426294197_at 0.00 3.03 0.00 2.40 3.38 0.00 UGCG D89866 102322_at 2.51 2.382.67 3.94 4.24 4.11 UGDH AF061017 95024_at 1.90 0.00 3.20 3.26 2.42 0.00USP18 AW047653 93305_f_at 0.00 0.00 5.69 4.47 3.95 3.50 VAMP8 AF053724100345_f_at 0.00 0.00 0.00 2.62 2.67 2.60 VAMP8 W65964 101982_at 0.001.36 0.00 2.45 2.66 2.27 stimulated X98475 phosphoprotein; 99799_at 1.443.13 0.00 2.64 2.99 2.40 vav oncogene; Vav X64361 96511_s_at 0.00 0.000.00 0.00 2.07 0.00 vav oncogene; Vav D83266 95490_at 0.00 0.00 0.002.26 3.00 2.09 UNK_AW120891 AW120891 92558_at 0.00 3.13 0.00 4.11 5.4911.07 VCAM1 M84487 92559_at 1.22 1.55 0.00 0.00 2.01 2.67 VCAM1 U1288492560_g_at 0.00 0.00 0.00 0.00 3.35 4.56 VCAM1 U12884 100084_at 0.000.00 0.00 0.00 2.73 3.56 villin 2; Vil2 X60671 101047_at 0.00 0.00 0.000.00 2.12 1.73 VIM AW123697 93337_at 0.00 0.00 0.00 2.13 1.83 2.11sorting 4b (yeast); U10119 Vps4b 98963_at 0.00 2.85 0.00 0.00 4.71 3.54VRL1 AB021665 100522_s_at 0.00 0.00 0.00 3.20 3.75 3.21 WW domainbinding U92454 protein 5; Wbp5 100523_r_at 0.00 0.00 0.00 2.41 3.13 2.02WW domain binding U92454 protein 5; Wbp5 103690_at 0.00 3.29 2.41 5.123.55 5.88 UNK_AW125574 AW125574 96075_at 0.00 2.11 0.00 3.70 2.89 3.37WDR1 AW060876 92262_at 0.00 0.00 0.00 0.00 3.19 0.00 WIG1 AF012923102044_at 0.00 2.42 3.42 11.06 23.81 19.33 ELM1 AF100777 102891_at 0.000.00 0.00 1.63 2.46 2.59 WRN D86527 113110_at 0.00 0.00 0.00 0.00 2.423.11 WRN AA960405 98946_at 0.00 1.87 0.00 4.72 3.95 3.55 UNK_AF033186AF033186 113094_at 0.00 0.00 0.00 0.00 3.83 0.00 UNK_AA175692 AA175692100958_at 0.00 0.00 0.00 0.00 4.56 7.64 UNK_AI647003 AI647003 99126_at0.00 0.00 0.00 0.00 2.03 3.61 inactive X specific L04961 transcripts;Xist 92665_f_at 0.00 0.00 0.00 0.00 1.94 2.01 regulated complex; X07967Xlr 100015_at 0.00 0.00 0.00 0.00 2.30 0.00 viral (v-yes) X67677oncogene homolog; Yes 104400_at 0.00 2.18 0.00 2.06 3.18 2.96UNK_AF076956 AF076956 97229_at 0.00 0.00 0.00 2.05 0.00 0.00UNK_AW061042 AW061042 97535_at 0.00 1.63 2.14 2.89 2.41 2.21monooxygenase/tryptophan D87661 5- monooxygenase activation protein, etapolypeptide; 97061_g_at 0.00 1.94 2.17 2.75 3.19 3.36 YWHAQ AW21548997544_at 0.00 1.72 0.00 2.31 3.14 2.92 YWHAZ D83037 92501_s_at 0.00 0.000.00 0.00 5.24 4.39 ZAC1 X95503 92502_at 0.00 0.00 0.00 1.40 7.40 6.62ZAC1 X95504 100475_at 0.00 0.00 0.00 3.36 2.20 2.88 zinc finger proteinD63902 147; Zfp147 92771_at 0.00 0.00 0.00 0.00 2.13 1.97 ZFP207AB013357 102277_at 0.00 0.00 0.00 0.00 2.59 0.00 ZFP26 M36514 92934_at0.00 0.00 0.00 0.00 2.66 0.00 zinc finger protein X79828 90; Zfp90103676_at 0.00 0.00 0.00 0.00 2.06 2.03 UNK_AI551306 AI551306

TABLE 2 Treatment BMP2 BMP2 BMP2 BMP2 BMP2 BMP2 Time day 01 day 02 day03 day 04 day 07 day 14 Affymetrix Avg. Fold Avg. Fold Avg. Fold Avg.Fold Avg. Fold Avg. Fold Genbank Qualifier Change Change Change ChangeChange Change Gene Name Accession # 115844_at −2.74 −4.65 −3.15 −2.76−2.12 −2.10 UNK_AI847028 AI847028 103494_at 0.00 −2.50 −3.42 −2.87 −4.24−2.99 UNK_AI047972 AI047972 104342_i_at 0.00 −4.22 −3.45 −5.08 −10.18−4.00 UNK_AI845798 AI845798 107074_at 0.00 −2.55 −2.53 −3.42 −4.39 −2.24UNK_AI838083 AI838083 133738_at 0.00 −2.30 −2.02 −3.17 −4.39 −3.23UNK_AI467229 AI467229 133932_at 0.00 −2.17 −2.06 −3.16 −4.05 −2.76UNK_AI503993 AI503993 133951_at 0.00 −3.22 −3.10 −10.36 −6.86 −2.39UNK_AI504979 AI504979 94534_at 0.00 −2.04 −2.11 0.00 −4.07 −2.36UNK_AI835446 AI835446 94790_at 0.00 −2.24 −2.48 0.00 −3.80 −2.57UNK_AA681807 AA681807 95468_at 0.00 −2.15 −1.91 −2.63 −4.12 −2.55 BTDAI850202 96391_at 0.00 −2.96 −2.60 −1.90 −3.00 −2.41 EST; unknown C80836105638_at 0.00 −3.95 −4.59 0.00 −10.36 −2.07 UNK_AA896641 AA896641106963_at 0.00 −2.48 −2.10 0.00 −3.26 −3.68 UNK_AW050323 AW050323107282_at 0.00 −2.07 −2.27 0.00 −4.69 −4.22 UNK_AW047933 AW047933107418_at 0.00 −2.16 0.00 −3.07 −5.71 −2.08 UNK_AW046245 AW046245107952_i_at 0.00 −2.62 −2.43 0.00 −2.93 −2.12 UNK_AA606601 AA606601109968_at 0.00 −5.91 −3.57 0.00 −8.76 −2.67 UNK_AA771415 AA771415110269_at −2.16 −5.45 −2.93 0.00 −3.03 0.00 UNK_AW045975 AW045975115109_at 0.00 −2.05 −1.79 −4.17 −4.31 −2.28 UNK_AI838503 AI838503115246_at 0.00 −1.95 −2.61 −3.31 −5.64 −2.62 UNK_AA790442 AA790442116614_at 0.00 −2.54 −2.37 0.00 −3.72 −2.01 UNK_AA647405 AA647405129661_at 0.00 −2.57 −3.45 0.00 −3.41 −2.12 UNK_AA792999 AA792999130718_at 0.00 −2.98 −2.27 0.00 −2.50 −2.32 UNK_AI844247 AI844247133977_at 0.00 −3.33 −2.14 −3.11 −2.79 −1.68 UNK_AI506633 AI506633135609_at 0.00 −2.66 0.00 −2.42 −4.25 −2.42 UNK_AI505553 AI50555393514_at 0.00 −2.76 −1.94 0.00 −4.77 −5.23 MYLC X12972 94418_at 0.00−2.71 −8.42 0.00 −2.51 −0.63 UNK_AI839004 AI839004 94908_r_at 0.00 0.00−2.19 0.00 −4.76 −2.57 UNK_AW045632 AW045632 95587_at 0.00 −2.33 −2.230.00 −2.97 −1.80 UNK_AI837204 AI837204 98942_r_at 0.00 −2.33 −3.05 0.00−3.93 −1.78 UNK_AW125284 AW125284 102862_at 0.00 0.00 −3.42 0.00 −3.42−3.17 UNK_AA873956 AA873956 102916_s_at 0.00 −4.25 −3.83 0.00 −2.86 0.00UNK_AB010266 AB010266 102922_at 0.00 −3.08 −2.52 0.00 −2.84 −1.50UNK_AI851387 AI851387 105610_at 0.00 0.00 −2.89 0.00 −4.34 −2.22UNK_AA388982 AA388982 106934_at 0.00 0.00 −2.79 0.00 −10.65 −4.94UNK_AW047806 AW047806 107569_at 0.00 −2.01 0.00 0.00 −2.37 −2.03UNK_AA738625 AA738625 110774_at 0.00 −3.03 −2.48 0.00 −2.45 −1.51UNK_AI852667 AI852667 111228_at 0.00 −1.68 −2.69 0.00 −2.72 −2.01UNK_AW122874 AW122874 111254_at 0.00 −2.06 −2.12 0.00 −3.40 −1.69UNK_AA735016 AA735016 111260_at 0.00 0.00 −2.66 0.00 −3.27 −3.11UNK_AI843809 AI843809 112012_at 0.00 −2.13 −2.12 0.00 −4.16 −1.67UNK_AI875092 AI875092 113124_at 0.00 −4.08 0.00 0.00 −8.64 −2.40UNK_AI852911 AI852911 113806_at 0.00 0.00 −2.69 0.00 −2.68 −2.20UNK_AW121611 AW121611 114138_at 0.00 0.00 −2.00 0.00 −5.82 −2.95UNK_AI643851 AI643851 114297_f_at 0.00 −1.96 −2.03 0.00 −4.33 −2.31UNK_AI021087 AI021087 114466_at 0.00 −1.89 −2.07 0.00 −3.21 −2.18UNK_AA197511 AA197511 116583_at 0.00 −2.08 −1.70 0.00 −3.36 −2.23UNK_AW121389 AW121389 116792_at 0.00 −1.94 −3.96 0.00 −4.51 −3.31UNK_AI480742 AI480742 129309_at 0.00 −2.55 −1.92 0.00 −3.86 −2.58UNK_AI596885 AI596885 129952_at 0.00 0.00 −2.17 0.00 −2.85 −2.68UNK_AI595378 AI595378 135181_f_at 0.00 −1.74 −1.70 −2.21 −3.48 −2.24UNK_AW125817 AW125817 139035_at 0.00 −2.05 0.00 −2.09 −2.40 0.00UNK_AI846518 AI846518 140572_at 0.00 −2.94 −2.45 0.00 −2.88 0.00UNK_AW125201 AW125201 92202_g_at 0.00 0.00 0.00 0.00 −3.21 −2.40UNK_AI553024 AI553024 92941_at 0.00 0.00 0.00 0.00 −3.70 −2.71UNK_AA833509 AA833509 93177_at 0.00 0.00 0.00 0.00 −3.03 −2.08UNK_AW121661 AW121661 93780_at 0.00 −2.35 −1.92 0.00 −2.37 −1.95UNK_AW060827 AW060827 95376_at 0.00 0.00 0.00 0.00 −5.44 −5.10UNK_AJ011107 AJ011107 95518_at 0.00 −2.12 −1.76 0.00 −2.06 0.00UNK_AW122893 AW122893 96211_at 0.00 0.00 0.00 −2.61 −4.19 0.00UNK_AI846896 AI846896 99331_at 0.00 0.00 0.00 0.00 −3.02 −4.46UNK_AW125581 AW125581 99503_at 0.00 −2.49 0.00 0.00 −2.85 −1.74UNK_AW045204 AW045204 100058_at 0.00 0.00 0.00 0.00 −2.34 −3.75UNK_AW047776 AW047776 103257_at 0.00 0.00 −1.75 0.00 −2.96 −2.37UNK_AA690483 AA690483 103665_at 0.00 −2.26 −5.60 0.00 −1.79 −0.73UNK_AW122523 AW122523 104153_at 0.00 0.00 0.00 0.00 −3.18 −2.04UNK_AW047743 AW047743 104293_at 0.00 0.00 −1.95 0.00 −2.61 −2.73UNK_AI882440 AI882440 104445_at −1.69 −3.53 −2.56 0.00 −1.65 0.00UNK_AW046694 AW046694 104491_at 0.00 −1.77 −2.21 0.00 −2.08 0.00UNK_AI509330 AI509330 104804_at 0.00 −1.61 0.00 0.00 −2.94 −2.31UNK_AI504570 AI504570 104944_at 0.00 0.00 0.00 0.00 −2.25 −2.14UNK_AA619815 AA619815 105168_at 0.00 −1.76 0.00 0.00 −2.67 −2.61UNK_AI847519 AI847519 105569_at 0.00 0.00 −1.98 0.00 −3.12 −3.32UNK_AI605044 AI605044 105619_at 0.00 0.00 0.00 0.00 −20.58 −7.69UNK_AI849242 AI849242 105706_at 0.00 0.00 0.00 0.00 −3.77 −2.26UNK_AI847342 AI847342 106065_at 0.00 −2.29 0.00 0.00 −2.40 0.00UNK_AI849096 AI849096 106297_at 0.00 −2.02 0.00 0.00 −2.32 0.00UNK_AI841521 AI841521 106439_at 0.00 0.00 0.00 0.00 −3.25 −3.88UNK_AI851838 AI851838 106505_at 0.00 −1.79 0.00 0.00 −2.85 −2.52UNK_AI844271 AI844271 106521_at 0.00 −2.23 0.00 0.00 −4.38 0.00UNK_AI987764 AI987764 106896_at 0.00 0.00 0.00 0.00 −2.96 −2.16UNK_AW049892 AW049892 107400_at 0.00 −2.00 −2.22 0.00 −1.83 0.00UNK_AW048204 AW048204 107427_at 0.00 −1.59 0.00 0.00 −3.02 −2.22UNK_AW122504 AW122504 107428_at 0.00 0.00 0.00 0.00 −2.66 −2.13UNK_AW046414 AW046414 108010_at 0.00 0.00 0.00 0.00 −3.82 −2.72UNK_AW210455 AW210455 108069_at 0.00 0.00 0.00 0.00 −2.51 −2.13UNK_AI642606 AI642606 108488_at 0.00 0.00 0.00 0.00 −2.80 −2.49UNK_AI838112 AI838112 108565_at 0.00 −2.68 −2.95 0.00 2.66 4.55UNK_AI853095 AI853095 108767_at 0.00 −2.42 0.00 0.00 −3.47 0.00UNK_AI448797 AI448797 108822_at 0.00 0.00 0.00 −3.70 −3.72 0.00UNK_AI615758 AI615758 109049_at 0.00 0.00 0.00 0.00 −3.89 −2.60UNK_AI643675 AI643675 109086_at 0.00 0.00 −1.83 0.00 −3.02 −2.24UNK_AI463271 AI463271 109488_at 0.00 0.00 0.00 0.00 −3.72 −3.74UNK_AW123076 AW123076 109774_at 0.00 −1.85 −1.71 0.00 −3.33 −2.06 PDK2AI848783 110330_at 0.00 −1.52 0.00 0.00 −4.15 −2.08 UNK_AI843917AI843917 111483_at 0.00 −1.37 0.00 0.00 −4.16 −3.11 UNK_AI451767AI451767 111525_at 0.00 0.00 0.00 0.00 −2.70 −2.28 UNK_AA289880 AA289880111547_at 0.00 0.00 0.00 0.00 −3.17 −2.26 UNK_AI851666 AI851666111970_at 0.00 −1.51 0.00 0.00 −4.74 −3.89 UNK_AI616223 AI616223112392_at 0.00 0.00 0.00 0.00 −4.82 −2.89 UNK_AI834768 AI834768112405_at 0.00 0.00 0.00 0.00 −5.07 −3.81 UNK_AI557974 AI557974112864_at 0.00 −1.75 −2.07 0.00 −2.50 0.00 UNK_AI849524 AI849524112986_at 0.00 0.00 0.00 0.00 −5.51 −5.79 UNK_AI849914 AI849914113545_at 0.00 −1.47 0.00 0.00 −2.87 −2.16 UNK_AI847141 AI847141113691_at 0.00 0.00 0.00 0.00 −3.69 −2.65 UNK_AW049533 AW049533114315_at 0.00 0.00 0.00 0.00 −2.70 −2.60 UNK_AW048818 AW048818114394_at 0.00 −2.13 0.00 0.00 −2.20 0.00 UNK_AW121080 AW121080114420_at 0.00 −3.91 −3.29 0.00 3.25 4.37 UNK_AA734866 AA734866114453_at 0.00 0.00 0.00 0.00 −4.76 −5.72 UNK_AI848077 AI848077114514_at 0.00 0.00 0.00 −2.37 −2.33 −1.99 UNK_AI605635 AI605635114553_at 0.00 0.00 0.00 0.00 −2.81 −2.15 UNK_AI414584 AI414584114556_at 0.00 −1.81 −1.54 0.00 −2.17 −2.03 UNK_AI451747 AI451747114685_at 0.00 −2.08 0.00 0.00 −2.83 0.00 UNK_AW123120 AW123120114743_at 0.00 0.00 0.00 0.00 −4.86 −4.13 UNK_AI591553 AI591553114775_at 0.00 0.00 0.00 0.00 −4.72 −2.22 UNK_AI005882 AI005882115070_at 0.00 0.00 −1.91 0.00 −4.34 −2.05 UNK_AA711252 AA711252115155_at 0.00 0.00 −1.72 0.00 −4.16 −3.45 UNK_AI853189 AI853189115199_at 0.00 0.00 0.00 0.00 −3.57 −2.34 UNK_AA667270 AA667270115201_at 0.00 0.00 0.00 0.00 −2.39 −2.04 UNK_AI851486 AI851486115236_at 0.00 −2.07 0.00 0.00 −3.28 −1.93 UNK_AA824120 AA824120115360_at 0.00 −1.81 0.00 0.00 −3.33 −2.68 UNK_AI839569 AI839569115467_at 0.00 0.00 0.00 0.00 −2.94 −2.13 UNK_AI852809 AI852809115539_at 0.00 −2.59 −1.92 0.00 −3.44 −1.93 UNK_AW045801 AW045801115575_at 0.00 0.00 0.00 0.00 −2.04 −2.26 UNK_AI853953 AI853953116042_at 0.00 0.00 −1.84 0.00 −3.19 −2.15 UNK_AI591726 AI591726116350_at 0.00 0.00 0.00 0.00 −5.09 −3.88 UNK_AA981270 AA981270116390_at 0.00 0.00 0.00 0.00 −3.43 −2.26 UNK_AI647836 AI647836116644_at 0.00 0.00 −1.97 0.00 −2.74 −2.31 UNK_AI882312 AI882312116747_at 0.00 −1.82 0.00 0.00 −3.27 −2.54 UNK_AI505458 AI505458116826_at 0.00 −1.98 −2.47 0.00 −4.71 −1.89 UNK_AA616199 AA616199117128_at 0.00 0.00 0.00 0.00 −2.27 −2.06 UNK_AI851602 AI851602117208_at 0.00 −1.93 −1.88 0.00 −3.27 −2.57 UNK_AI838208 AI838208117242_at 0.00 0.00 0.00 0.00 −5.22 −2.68 UNK_AI835553 AI835553117280_at 0.00 0.00 0.00 0.00 −4.97 −5.55 UNK_AI835075 AI835075128785_r_at 0.00 −2.02 0.00 0.00 −4.18 −1.97 UNK_AI049307 AI049307128829_at 0.00 −1.71 0.00 −1.71 −2.81 −2.11 UNK_AA624027 AA624027129503_at 0.00 −1.69 0.00 0.00 −3.59 −2.12 UNK_AI893884 AI893884129544_at 0.00 0.00 0.00 0.00 −3.45 −2.71 UNK_AI156198 AI156198130460_at 0.00 0.00 0.00 0.00 −2.29 −2.22 UNK_AI836434 AI836434130990_at 0.00 0.00 0.00 0.00 −2.19 −2.38 UNK_AW047063 AW047063131264_f_at 0.00 0.00 0.00 0.00 −2.03 −2.23 UNK_AA466676 AA466676132021_at 0.00 0.00 0.00 0.00 −2.04 −2.33 UNK_AI429239 AI429239132820_at 0.00 −2.10 0.00 −2.44 0.00 0.00 UNK_AI639670 AI639670133719_f_at 0.00 0.00 0.00 0.00 −2.62 −2.46 UNK_AI463563 AI463563133720_at 0.00 −1.88 0.00 0.00 −2.73 −3.37 UNK_AI464129 AI464129133838_at 0.00 −1.90 0.00 −2.11 −2.82 0.00 UNK_AA420328 AA420328134116_at 0.00 0.00 0.00 0.00 −2.70 −2.28 UNK_AI255188 AI255188135201_at 0.00 −3.44 −2.08 0.00 2.29 3.08 UNK_AA420078 AA420078136088_at 0.00 0.00 0.00 0.00 −2.93 −2.72 UNK_AI551047 AI551047136348_at 0.00 0.00 −1.98 0.00 −3.82 −3.36 UNK_AW146057 AW146057136535_at 0.00 0.00 −1.79 0.00 −2.03 −2.06 UNK_AI642422 AI642422137185_l_at 0.00 0.00 0.00 0.00 −2.57 −2.24 UNK_AI840674 AI840674138502_at 0.00 0.00 0.00 0.00 −2.66 −3.02 UNK_AI847438 AI847438139022_at 0.00 0.00 −1.88 0.00 −3.62 −2.20 UNK_AI427762 AI427762140015_at 0.00 0.00 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110290_at 0.00 0.00 0.00 0.00 0.00 −3.55UNK_AW122616 AW122616 110292_at 0.00 0.00 0.00 0.00 −2.79 0.00 D9UCLA2AI839742 110361_at 0.00 −1.63 −1.39 0.00 −3.08 −1.93 UNK_AI839531AI839531 110442_at 0.00 0.00 0.00 0.00 −2.09 −1.65 UNK_AA960476 AA960476110529_at 0.00 0.00 0.00 0.00 −2.21 −1.70 UNK_AI594683 AI594683110644_s_at 0.00 −1.12 −5.38 0.00 0.00 0.00 UNK_AI593562 AI593562110673_at 0.00 0.00 0.00 0.00 −2.03 0.00 UNK_W53698 W53698 110755_at0.00 0.00 −2.59 0.00 −1.61 0.00 UNK_AI842126 AI842126 110757_at 0.000.00 0.00 0.00 −2.17 −1.85 UNK_AI847218 AI847218 110770_at 0.00 0.000.00 0.00 −2.06 0.00 UNK_AW045392 AW045392 110812_at 0.00 0.00 0.00 0.00−2.87 −1.60 UNK_AI836721 AI836721 110826_at 0.00 0.00 −1.80 0.00 −2.02−1.66 UNK_AW122152 AW122152 110972_at 0.00 0.00 0.00 −1.92 −2.38 −1.71UNK_AI848760 AI848760 111305_at 0.00 −1.67 0.00 0.00 −2.84 −1.80UNK_AW121459 AW121459 111359_at 0.00 −1.57 0.00 0.00 −3.83 −1.58UNK_AW108291 AW108291 111382_at 0.00 0.00 0.00 0.00 −2.03 0.00UNK_AI835341 AI835341 111431_at 0.00 −1.91 −1.68 0.00 −4.69 −1.78UNK_AI836555 AI836555 111445_at 0.00 0.00 0.00 0.00 −2.41 −1.61UNK_AW046417 AW046417 111517_at 0.00 0.00 0.00 0.00 −2.09 0.00UNK_AA983096 AA983096 111548_g_at 0.00 0.00 0.00 0.00 −2.90 −2.00UNK_AI851666 AI851666 111613_at 0.00 −1.36 0.00 0.00 −2.33 −1.44UNK_AW228205 AW228205 111689_at 0.00 0.00 0.00 0.00 −2.18 0.00UNK_AW060751 AW060751 111690_at 0.00 0.00 0.00 0.00 −2.27 0.00UNK_AW125187 AW125187 111947_at 0.00 0.00 0.00 0.00 −2.29 0.00UNK_AA789365 AA789365 112029_at 0.00 0.00 0.00 0.00 −2.61 −1.65UNK_AA821545 AA821545 112063_at 0.00 0.00 0.00 0.00 −2.86 0.00UNK_AA420218 AA420218 112073_at 0.00 0.00 0.00 0.00 −3.03 0.00UNK_AA242716 AA242716 112081_at 0.00 0.00 0.00 0.00 −2.25 −1.64UNK_AI510428 AI510428 112220_at 0.00 0.00 −2.37 0.00 0.00 0.00UNK_AA763894 AA763894 112318_at 0.00 0.00 0.00 0.00 −2.38 −1.55UNK_AW122090 AW122090 112336_at 0.00 −2.56 0.00 0.00 0.00 0.00UNK_AI854546 AI854546 112352_at 0.00 0.00 0.00 0.00 −2.08 0.00UNK_AI841571 AI841571 112363_at 0.00 0.00 0.00 0.00 −3.06 −1.80UNK_AW048194 AW048194 112381_at 0.00 −1.69 −2.32 0.00 0.00 0.00UNK_AA863867 AA863867 112398_at 0.00 0.00 0.00 0.00 −4.67 0.00UNK_AW045591 AW045591 112406_at 0.00 0.00 0.00 0.00 −2.71 −1.61UNK_AI851470 AI851470 112415_at 0.00 0.00 0.00 0.00 −2.06 −1.58UNK_AI604376 AI604376 112432_at 0.00 0.00 0.00 0.00 −2.38 0.00UNK_AW045567 AW045567 112668_at 0.00 0.00 0.00 0.00 −2.48 0.00UNK_AW261533 AW261533 112722_at 0.00 0.00 0.00 0.00 0.00 −2.59UNK_AW124381 AW124381 112820_at 0.00 −1.53 0.00 0.00 −3.27 −1.49UNK_AW045244 AW045244 112920_at 0.00 0.00 0.00 0.00 −7.87 0.00UNK_AW125065 AW125065 112947_at 0.00 0.00 0.00 0.00 −3.08 −1.87UNK_AA693298 AA693298 113012_at 0.00 −1.77 −1.53 0.00 −4.20 −1.84UNK_AI846919 AI846919 113210_at 0.00 −1.92 0.00 0.00 −2.72 −0.66UNK_AI841042 AI841042 113232_at 0.00 0.00 0.00 0.00 −2.36 0.00UNK_AI841061 AI841061 113314_at 0.00 0.00 0.00 0.00 −2.73 −1.77UNK_AI840767 AI840767 113318_at 0.00 0.00 0.00 0.00 −2.72 −1.78UNK_AW261686 AW261686 113330_at 0.00 0.00 0.00 0.00 −2.01 −0.45UNK_AI527630 AI527630 113565_at 0.00 0.00 0.00 0.00 −2.22 0.00UNK_AW049089 AW049089 113604_at 0.00 −1.61 0.00 0.00 −2.40 0.00UNK_AI847956 AI847956 113638_at 0.00 0.00 0.00 0.00 −2.45 −1.83UNK_AW045993 AW045993 113715_at 0.00 −1.98 0.00 0.00 −2.01 −1.62UNK_AA822301 AA822301 113785_at 0.00 0.00 −1.72 0.00 −2.43 −1.66UNK_AI850504 AI850504 113901_at 0.00 0.00 0.00 0.00 −1.89 −2.14UNK_AI593827 AI593827 113938_at 0.00 0.00 0.00 0.00 −4.11 0.00UNK_AI842866 AI842866 113985_at −2.17 0.00 0.00 0.00 0.00 0.00UNK_AI838258 AI838258 113986_at 0.00 −1.99 0.00 0.00 −2.92 0.00UNK_AI510303 AI510303 113990_at 0.00 0.00 0.00 0.00 −2.03 0.00UNK_AA763276 AA763276 113998_at 0.00 0.00 0.00 0.00 0.00 −2.00UNK_AA416235 AA416235 114069_at 0.00 0.00 0.00 0.00 −2.72 −1.86UNK_AI844797 AI844797 114093_at 0.00 0.00 0.00 0.00 −2.00 0.00UNK_AI852806 AI852806 114143_at 0.00 0.00 0.00 0.00 −2.11 0.00UNK_AI853600 AI853600 114296_at 0.00 0.00 0.00 0.00 −2.72 −1.42UNK_AA823920 AA823920 114316_at 0.00 0.00 0.00 0.00 −2.92 −1.69UNK_AI605358 AI605358 114392_at 0.00 0.00 0.00 0.00 −2.85 0.00UNK_AW120619 AW120619 114416_at 0.00 0.00 0.00 0.00 0.00 −3.51UNK_AW045985 AW045985 114418_at 0.00 0.00 0.00 0.00 −2.38 0.00UNK_AI854454 AI854454 114476_at 0.00 0.00 0.00 0.00 −2.89 0.00UNK_AI482420 AI482420 114478_at 0.00 0.00 0.00 0.00 0.00 −3.17UNK_AA061949 AA061949 114706_at 0.00 0.00 0.00 0.00 −2.32 −1.36UNK_AW049085 AW049085 114752_at 0.00 −2.01 0.00 0.00 0.00 2.84UNK_AI843572 AI843572 114794_at 0.00 −1.73 0.00 0.00 −2.33 −1.39UNK_AA693185 AA693185 114982_at 0.00 −1.59 0.00 0.00 −3.53 −1.98UNK_AA959852 AA959852 115077_f_at 0.00 0.00 0.00 0.00 −2.03 0.00 DBTAA896722 115078_r_at 0.00 0.00 0.00 0.00 −2.52 0.00 DBT AA896722115106_at 0.00 −1.49 0.00 0.00 −2.69 −1.92 UNK_AI851210 AI851210115169_at 0.00 0.00 0.00 0.00 −2.15 0.00 UNK_AW047351 AW047351 115323_at0.00 0.00 −1.34 0.00 −2.07 −1.72 UNK_AA107507 AA107507 115370_at 0.000.00 0.00 0.00 −2.38 0.00 UNK_AI527642 AI527642 115376_at 0.00 0.00 0.000.00 −2.23 0.00 UNK_AI850511 AI850511 115428_at 0.00 0.00 −1.95 0.00−3.82 0.00 UNK_AA673260 AA673260 115437_at 0.00 −1.66 0.00 0.00 −2.21−1.37 UNK_AW049924 AW049924 115545_at 0.00 0.00 0.00 0.00 −2.29 0.00UNK_AA940371 AA940371 115629_at 0.00 0.00 0.00 0.00 0.00 −3.06UNK_AA183896 AA183896 115640_at 0.00 0.00 0.00 0.00 −2.88 −0.66UNK_AI451541 AI451541 115686_at 0.00 0.00 0.00 0.00 −3.34 0.00UNK_AI853521 AI853521 115845_at 0.00 0.00 0.00 0.00 −2.24 −1.49UNK_AW107813 AW107813 115847_l_at 0.00 0.00 0.00 0.00 −2.07 −1.59UNK_AI327072 AI327072 116046_at 0.00 0.00 0.00 0.00 −2.42 0.00UNK_AI848153 AI848153 116151_at 0.00 0.00 −2.09 0.00 0.00 0.00UNK_AI845734 AI845734 116152_at 0.00 0.00 0.00 0.00 −5.30 −1.89UNK_AI840320 AI840320 116263_at 0.00 0.00 0.00 0.00 −2.20 −1.49UNK_AW060609 AW060609 116349_at 0.00 0.00 0.00 0.00 −2.01 0.00UNK_AI155885 AI155885 116406_at 0.00 0.00 0.00 0.00 0.00 −2.81UNK_AW050231 AW050231 116438_at 0.00 0.00 0.00 0.00 0.00 −2.92UNK_AI853912 AI853912 116466_at 0.00 0.00 0.00 0.00 −2.94 −1.80UNK_AI591541 AI591541 116661_at 0.00 0.00 0.00. 0.00 −2.81 0.00UNK_AI594516 AI594516 116771_at 0.00 0.00 0.00 0.00 −2.16 −1.56UNK_AI843862 AI843862 116856_at 0.00 0.00 0.00 0.00 −2.08 0.00UNK_AW122439 AW122439 116887_at 0.00 0.00 0.00 0.00 −2.49 0.00UNK_AI848169 AI848169 116919_f_at 0.00 0.00 0.00 0.00 −3.43 −1.62UNK_AI837430 AI837430 116949_at 0.00 0.00 0.00 0.00 −2.30 −1.95UNK_AI835398 AI835398 116967_at 0.00 0.00 0.00 0.00 −2.74 −1.58UNK_AI851900 AI851900 116975_at 0.00 0.00 0.00 0.00 0.00 −2.24UNK_AI848908 AI848908 117008_at 0.00 0.00 0.00 0.00 −2.41 0.00UNK_AI836364 AI836364 117080_at 0.00 0.00 0.00 0.00 −4.41 −1.77UNK_AW046827 AW046827 117107_at 0.00 −1.73 −1.97 0.00 −3.77 −1.76UNK_AI837768 AI837768 117123_at 0.00 −2.18 0.00 0.00 −1.51 0.00UNK_AI840704 AI840704 117125_at 0.00 0.00 −0.03 0.00 −3.36 −0.88UNK_AI835705 AI835705 117178_at 0.00 0.00 0.00 0.00 −2.32 −1.81UNK_AI844448 AI844448 117206_at 0.00 0.00 0.00 0.00 −5.29 0.00UNK_AW122028 AW122028 117213_at 0.00 −1.74 0.00 0.00 −3.01 −1.60UNK_AI850929 AI850929 117307_at 0.00 0.00 0.00 0.00 −3.93 0.00UNK_AI844588 AI844588 117308_at 0.00 0.00 0.00 0.00 −2.09 0.00UNK_AI835357 AI835357 128879_f_at 0.00 0.00 0.00 0.00 −3.24 0.00UNK_AI838074 AI838074 129016_f_at 0.00 0.00 0.00 0.00 −1.50 −2.09UNK_AI596402 AI596402 129176_at 0.00 0.00 0.00 0.00 0.00 −13.63UNK_AI607324 AI607324 129231_at 0.00 −5.11 0.00 0.00 0.00 0.00UNK_AW046840 AW046840 129306_r_at 0.00 0.00 0.00 0.00 −2.42 −1.86UNK_AI606549 AI606549 129582_at 0.00 0.00 0.00 0.00 −2.32 −1.74UNK_AI465103 AI465103 130312_at 0.00 0.00 0.00 0.00 −1.96 −2.85UNK_AW215796 AW215796 130512_at 0.00 −1.69 0.00 0.00 −2.50 −1.87UNK_AI848603 AI848603 130696_f_at 0.00 0.00 0.00 −3.94 0.00 0.00UNK_AW210623 AW210623 130730_f_at 0.00 0.00 0.00 0.00 −1.91 −2.09UNK_AA270325 AA270325 132118_at 0.00 −1.73 0.00 −2.16 −1.93 −1.94UNK_AI642706 AI642706 133171_at 0.00 −2.00 −1.80 0.00 0.00 0.00UNK_AA683786 AA683786 133759_at 0.00 0.00 0.00 0.00 −2.61 0.00UNK_AI480951 AI480951 133886_at 0.00 0.00 0.00 0.00 −4.76 0.00UNK_AA168908 AA168908 134047_at 0.00 −1.88 0.00 0.00 −2.17 −1.74UNK_AW123320 AW123320 134281_at 0.00 0.00 0.00 0.00 −2.51 0.00UNK_AI551165 AI551165 134622_f_at −2.30 0.00 0.00 0.00 0.00 0.00UNK_AI641962 AI641962 134778_at 0.00 −1.98 −1.91 0.00 −2.80 −1.87UNK_AI666678 AI666678 135643_at 0.00 −2.73 0.00 0.00 0.00 0.00UNK_AA396310 AA396310 135691_at 0.00 −1.77 0.00 0.00 −2.36 −1.46UNK_AA882067 AA882067 136174_at 0.00 0.00 −1.68 0.00 −2.11 −1.50UNK_AW048956 AW048956 136545_at 0.00 −4.44 −1.77 0.00 −1.82 0.00UNK_AA982069 AA982069 136719_at 0.00 0.00 0.00 0.00 −2.50 0.00UNK_AI847908 AI847908 137973_at 0.00 −1.94 −1.65 0.00 −3.24 −1.85UNK_AI843877 AI843877 137979_at 0.00 −2.19 0.00 0.00 0.00 0.00UNK_AI848070 AI848070 138060_at 0.00 0.00 0.00 0.00 −2.00 0.00UNK_AW122571 AW122571 138086_f_at 0.00 0.00 0.00 0.00 −1.73 −2.25UNK_AW122816 AW122816 138556_at 0.00 0.00 0.00 0.00 0.00 −2.27UNK_AI874931 AI874931 139522_at 0.00 −1.48 0.00 0.00 −2.07 −1.56UNK_AW046420 AW046420 139980_g_at 0.00 0.00 0.00 0.00 −3.05 −1.67UNK_AI450646 AI450646 140519_at 0.00 0.00 0.00 0.00 −2.68 −1.97UNK_AI642378 AI642378 140861_at 0.00 −2.29 0.00 0.00 −1.43 0.00UNK_AI645591 AI645591 104962_at 0.00 0.00 0.00 0.00 0.78 −3.35 AA450473AA450473 93316_at 0.00 0.00 0.00 0.00 −2.00 0.00 UNK_AB017026 AB01702697172_s_at 0.00 0.00 0.00 0.00 −2.07 0.00 ABCC9 D86037 95425_at 0.000.00 0.00 0.00 −2.24 0.00 acetyl-Coenzyme A U21489 dehydrogenase, long-chain; Acadl 92581_at 0.00 0.00 −1.93 0.00 −2.49 0.00 acetyl-Coenzyme AU07159 dehydrogenase, medium chain; Acadm 106070_at 0.00 0.00 −3.56 0.00−4.60 0.00 UNK_AI854239 AI854239 104650_at 0.00 0.00 0.00 0.00 0.00−8.36 acetylcholinesterase; X56518 Ache 101515_at 0.00 0.00 0.00 0.00−2.32 0.00 acyl-Coenzyme A AF006688 oxidase; Acox- pending 101028_i_at0.00 −1.72 −3.47 0.00 −3.72 −2.05 actin, alpha, cardiac; M15501 Actc193903_at 0.00 0.00 0.00 0.00 −3.07 0.00 activin receptor IIB; M84120Acvr2b 99671_at 0.00 −1.93 −2.01 0.00 0.00 1.51 adipsin; Adn X0467398999_at 0.00 0.00 0.00 0.00 −2.64 −1.88 ADSL AA606587 98435_at 0.000.00 0.00 0.00 −2.43 −2.03 adenylosuccinate M74495 synthetase 1, muscle;Adss1 111708_at 0.00 0.00 0.00 0.00 −2.33 −1.94 AF180471 AA70994497279_at 0.00 0.00 0.00 0.00 −2.14 0.00 UNK_AI837615 AI837615 110392_at0.00 0.00 0.00 0.00 −2.20 0.00 UNK_AA789854 AA789854 112429_at −1.97−1.95 −1.77 0.00 −2.77 0.00 UNK_AI462012 AI462012 112387_at 0.00 −2.450.00 0.00 −3.22 −2.31 UNK_AI747215 AI747215 99521_at 0.00 0.00 0.00 0.00−2.53 0.00 AK4 AB020239 92768_s_at 0.00 0.00 −2.85 −2.29 0.00 0.00aminolevulinic acid M15268 synthase 2, erythroid; Alas2 93500_at 0.000.00 0.00 0.00 −2.08 0.00 0 M63245 100068_at 0.00 −1.88 0.00 0.00 −3.32−1.91 alcohol M74570 dehydrogenase family 1, subfamily A2; Aldh1a2101489_at 0.00 0.00 0.00 0.00 −2.09 −2.05 AMD1 D12780 100323_at 0.000.00 −1.91 0.00 −2.12 0.00 AMD2 Z23077 100324_g_at 0.00 0.00 0.00 0.00−2.21 −1.84 AMD2 Z23077 101058_at 0.00 0.00 −2.85 0.00 −2.87 −2.06 AMY1J00356 100440_f_at 0.00 0.00 0.00 0.00 −3.30 −2.28 ANK1 U76758100441_s_at 0.00 0.00 0.00 0.00 −5.39 −2.20 ANK1 X69064 100439_l_at 0.000.00 0.00 0.00 −2.65 −1.95 ANK1 U76758 98476_at 0.00 0.00 −1.74 0.00−2.10 0.00 ANK3 L40631 98477_s_at 0.00 −1.84 0.00 0.00 −3.34 −1.89ankyrin 3, epithelial; L40632 Ank3 97786_at −1.75 0.00 0.00 0.00 −2.14−1.51 UNK_AJ011118 AJ011118 97235_f_at 0.00 −1.80 −2.29 0.00 −3.50 0.00APOBEC2 AW124988 93592_at −1.50 −3.36 0.00 0.00 0.00 0.00 apolipoproteinD; X82648 Apod 109808_at 0.00 0.00 0.00 0.00 −3.03 0.00 APOE AI504617102704_at −0.92 −4.95 −3.29 −4.01 −5.56 −3.77 aquaporin 4; Aqp4 U88623102703_s_at 0.00 −2.91 0.00 0.00 −3.94 −2.23 AQP4 U48398 102382_at 0.000.00 0.00 0.00 0.00 −2.46 ARNTL AB014494 99481_at 0.00 0.00 −1.98 0.00−2.90 −2.33 UNK_AI839697 AI839697 93664_at 0.00 0.00 0.00 0.00 0.00−2.07 ATP1B2 X16645 99570_s_at 0.00 −2.68 −1.76 −2.81 −1.98 0.00 ATP2A2AF029982 103699_i_at 0.00 −2.48 −3.08 0.00 −3.36 −2.40 UNK_AI646638AI646638 96035_at 0.00 0.00 −2.13 0.00 −2.59 −1.68 branched chain L47335ketoacid dehydrogenase E1, alpha polypeptide; Bckdha 102302_at 0.00 0.00−1.89 0.00 −2.21 0.00 BCKDHB L16992 103015_at 0.00 0.00 0.00 0.00 −2.040.00 B-cell U41465 leukemia/lymphoma 6; Bcl6 93836_at 0.00 −2.58 −2.530.00 −3.95 −1.74 BNIP3 AF041054 101903_at 0.00 0.00 0.00 0.00 −3.93−2.66 CD8beta opposite U76371 strand; Bop 94815_at 0.00 −1.91 −2.05 0.00−3.33 0.00 2,3- X13586 bisphosphoglycerate mutase; Bpgm 113861_at 0.000.00 0.00 0.00 −2.15 −1.61 BVES-PENDING AI152383 101128_at 0.00 0.000.00 0.00 −2.93 −2.12 calcium channel, L06234 voltage-dependent, L type,alpha 1S subunit; Cacna1s 99812_at 0.00 −1.79 0.00 0.00 −2.40 −2.09calpain 3; Capn3 X92523 99813_g_at 0.00 0.00 0.00 0.00 −2.54 −2.11calpain 3; Capn3 X92523 98079_at −2.36 −4.93 0.00 0.00 −13.32 −6.68CAR14 AB005450 92642_at 0.00 0.00 −2.16 0.00 −2.62 5.27 CAR2 M25944100600_at 0.00 0.00 0.00 0.00 −2.40 −2.04 CD24A M58661 93332_at 0.000.00 0.00 0.00 −2.65 −1.74 CD36 antigen; Cd36 L23108 101516_at 0.00 0.00−2.01 0.00 0.00 0.00 CD59 U60473 104743_at 0.00 0.00 0.00 0.00 −2.26−2.14 UNK_AB022100 AB022100 95471_at 0.00 −2.68 −2.76 0.00 2.10 1.92cyclin-dependent U22399 kinase inhibitor 1C (P57); Cdkn1c 104209_at 0.000.00 0.00 0.00 −6.63 −3.70 CHRP AI847016 99994_at 0.00 0.00 −2.89 0.51−3.44 0.00 CIDEA AF041376 94463_at 0.00 0.00 0.00 0.00 −5.15 0.00chloride channel 3; X78874 Clcn3 94464_at 0.00 −1.75 0.00 0.00 −2.12−1.59 CLCN3 AF029347 94465_g_at 0.00 0.00 0.00 0.00 −2.01 −1.32 CLCN3AF029347 92322_at 0.00 0.00 −2.94 −1.65 −2.57 0.00 cathelin-likeprotein; X94353 Cnlp 93582_at 0.00 0.00 0.00 0.00 −2.10 0.00 COQ7AF080580 102749_at 0.00 0.00 −1.45 0.00 −2.37 −1.32 COX7A1 AF037370113828_at 0.00 −2.35 −2.07 0.00 −4.31 −2.24 CPT1B AA189179 102951_at0.00 0.00 0.00 0.00 0.00 −2.03 CRADD AJ224738 103646_at 0.00 0.00 −1.750.00 −2.43 −1.81 carnitine X85983 acetyltransferase; Crat 99065_at 0.000.00 0.00 −2.08 0.00 0.00 casein kappa; Csnk M10114 97336_at 0.00 −2.650.00 0.00 0.00 2.12 UNK_AJ131851 AJ131851 98132_at 0.00 0.00 0.00 0.00−3.97 0.00 cytochrome c, X01756 somatic; Cycs 93996_at 0.00 −4.02 −5.63−4.92 −3.73 0.00 CYP2E1 X01026 94526_at 0.00 0.00 0.00 0.00 −2.34 0.00UNK_AI848453 AI848453 96757_at 0.00 0.00 −2.06 0.00 −3.05 −1.95D10JHU81E AI852165 109645_at 0.00 0.00 0.00 0.00 −2.03 −1.59UNK_AW123377 AW123377 113324_at 0.00 0.00 0.00 0.00 −2.47 0.00UNK_AI121830 AI121830 96803_at 0.00 0.00 0.00 0.00 −2.32 0.00UNK_AW210370 AW210370 96346_at 0.00 −1.46 −2.12 0.00 2.45 5.93 D18UCLA3AI854020 133703_at 0.00 0.00 0.00 0.00 −2.52 −2.07 UNK_AI462192 AI46219295594_at 0.00 −2.01 −2.26 0.00 −2.86 −2.01 UNK_AI847486 AI84748693614_at 0.00 0.00 0.00 0.00 −4.05 −4.34 UNK_AA600647 AA600647 99959_at0.00 0.00 0.00 0.00 −2.42 0.00 UNK_AW061337 AW061337 97397_at 0.00 0.000.00 0.00 −2.35 −1.50 UNK_AI848344 AI848344 113212_at 0.00 0.00 0.000.00 −4.09 −1.85 UNK_AI848538 AI848538 102859_at 0.00 −1.90 0.00 0.00−2.02 −1.80 UNK_AW121304 AW121304 96112_at 0.00 0.00 0.00 0.00 −2.150.00 UNK_AI851178 AI851178 112421_at 0.00 −2.29 0.00 0.00 −6.07 −3.49UNK_AI838528 AI838528 103617_at 0.00 0.00 0.00 0.00 −2.42 0.00 decayaccelerating D63679 factor 1; Daf1 98966_at 0.00 0.00 0.00 0.00 −2.58−0.74 dihydrolipoamide L42996 branched chain transacylase E2; Dbt98527_at 0.00 −2.22 0.00 0.00 −3.37 −2.02 dodecenoyl- Z14050 Coenzyme Adelta isomerase (3,2 trans- enoyl-Coenyme A isomerase); Dci 95478_at0.00 0.00 0.00 0.00 −2.07 −1.81 DEB1 AW124231 99485_at 0.00 0.00 0.000.00 −2.08 0.00 DFFA AB009376 108255_at 0.00 0.00 0.00 0.00 −2.29 −2.60DUSP13 AA144705 100311_f_at 0.00 0.00 −2.37 0.00 0.00 0.00 EAR1 U72032103240_f_at 0.00 0.00 −3.40 0.00 0.00 0.00 EAR3 AF017258 93754_at 0.000.00 0.00 0.00 −2.05 0.00 enoyl coenzyme A AF030343 hydratase 1,peroxisomal; Ech1 102774_at 0.00 −1.77 0.00 0.00 −2.89 −1.98 epidermalgrowth V00741 factor; Egf 94353_at 0.00 0.00 0.00 0.00 0.00 −2.24eukaryotic U75530 translation initiation factor 4E binding protein 2;Eif4ebp2 93051_at 0.00 −2.61 0.00 0.00 −2.14 0.00 EPHX2 Z37107101538_l_at 0.00 −4.79 −3.78 0.00 −7.47 −1.63 ES1 AW226939 101539_f_at0.00 −3.93 −3.37 0.00 −7.31 0.00 ES1 AW226939 103964_at 0.00 −1.62 −1.630.00 −2.22 0.00 estrogen related U85259 receptor, alpha; Esrra 115969_at0.00 0.00 0.00 0.00 −2.50 0.00 EXTL1 AI850861 94214_at 0.00 −2.71 0.000.00 −3.30 0.00 FABP3 X14961 94507_at 0.00 0.00 0.00 0.00 −2.62 0.00fatty acid Coenzyme U15977 A ligase, long chain 2; Facl2 98575_at 0.00−1.34 −3.15 −2.39 −3.33 0.00 fatty acid synthase; X13135 Fasn 100928_at−4.16 0.00 0.00 2.21 −0.01 19.58 fibulin 2; Fbln2 X75285 97379_at −0.89−3.22 −4.99 0.00 −7.21 −4.72 fructose D42083 bisphosphatase 2; Fbp297518_at 0.00 −3.76 −2.66 0.00 −2.48 −1.86 famesyl diphosphate D29016famesyl transferase 1; Fdft1 92587_at 0.00 0.00 0.00 0.00 −2.01 0.00ferredoxin 1; Fdx1 L29123 97213_at 0.00 −2.01 −2.18 0.00 −3.49 −2.34FEM1A AF064447 100494_at 0.00 0.00 0.00 0.00 −3.74 0.00 FGF1 M30641103995_at 0.00 0.00 0.00 0.00 −2.00 −2.32 FGFBP1 AF065441 102366_at 0.000.00 −5.06 −3.75 0.00 2.31 UNK_AA718169 AA718169 101991_at 0.00 −2.610.00 0.00 −1.59 1.77 flavin containing D16215 monooxygenase 1; Fmo1104607_at 0.00 0.00 −1.82 0.00 −2.08 −1.72 UNK_AF093624 AF09362499121_at 0.00 0.00 0.00 0.00 −2.20 0.00 fragile X mental X90875retardation gene, autosomal homolog; Fxr1h 97430_at 0.00 −2.17 0.00 0.00−3.62 −2.00 G6PT1 AF080469 104616_g_at 0.00 0.00 0.00 0.00 −3.11 0.00galactose-1- M96265 phosphate uridyl transferase; Galt 102967_at 0.000.00 0.00 −1.64 −2.62 −2.68 GDAP1 Y17850 92592_at 0.00 0.00 0.00 0.00−3.62 −2.07 GDC1 M25558 97155_at −1.62 0.00 0.00 0.00 −4.30 −2.94myostatin; Mstn U84005 98984_f_at 0.00 0.00 0.00 0.00 −5.39 −2.75glycerol phosphate D50430 dehydrogenase 1, mitochondrial; Gdm1 99107_at0.00 −2.02 0.00 0.00 −1.80 0.00 GHR M31680 102060_at 0.00 −2.08 0.000.00 −1.92 −1.63 GOLGA4 AF051357 100573_f_at 0.00 −1.98 −1.95 0.00 −2.35−1.80 GPI1 M14220 113915_at 0.00 −2.92 −3.65 −4.26 −4.95 −3.03UNK_AI226254 AI226254 93750_at 0.00 −2.13 −2.15 0.00 −1.75 0.00gelsolin; Gsn J04953 112869_at 0.00 0.00 0.00 0.00 −2.44 −2.45GSNPAT-PENDING AI852572 96085_at 0.00 0.00 0.00 0.00 0.00 −2.36 GSTA4L06047 93543_f_at 0.00 0.00 −1.85 0.00 −2.20 0.00 GSTM1 J03952102094_f_at 0.00 0.00 0.00 0.00 −3.22 −1.46 GSTM1 AI841270 95445_at 0.000.00 0.00 0.00 −1.96 −2.10 GUKMI1 AW124194 100597_at 0.00 0.00 0.00 0.00−2.22 0.00 GYG1 AW049730 98496_at 0.00 −2.01 0.00 0.00 −2.49 −1.83 GYS3U53218 95485_at 0.00 0.00 −1.89 0.00 −2.61 0.00 hydroxylacyl- D29639Coenzyme A dehydrogenase- dehydrogenase; Hadh 94781_at −1.29 −1.94 −2.84−2.71 −1.65 0.00 hemoglobin alpha, V00714 adult chain 1; Hba- a1103534_at −1.77 −1.81 −3.81 0.00 −2.23 1.56 hemoglobin, beta V00722adult minor chain; Hbb-b2 94375_at 0.00 0.00 0.00 0.00 −2.10 −1.94hexokinase 2; Hk2 Y11666 92568_at 0.00 0.00 0.00 0.00 −1.92 −2.02house-keeping M74555 protei 1; Hkp1 102714_at 0.00 0.00 0.00 0.00 −1.87−2.08 HSC70T L27086 97867_at 0.00 −2.03 0.00 0.00 0.00 0.00hydroxysteroid 11- X83202 beta dehydrogenase 1; Hsd11b1 102620_at 0.000.00 0.00 0.00 −7.64 −4.63 UNK_AF088983 AF088983 97914_at 0.00 0.00 0.000.00 −2.02 −1.92 heat shock protein, D17666 74 kDa, A; Hspa9a 95693_at0.00 −2.56 −2.35 0.00 −2.04 −1.82 isocitrate U51167 dehydrogenase 2(NADP+), mitochondrial; Idh2 93029_at 0.00 0.00 0.00 0.00 −2.22 0.00isocitrate U68564 dehydrogenase 3 (NAD+), gamma; Idh3g 103904_at 0.00−2.69 −2.38 0.00 0.00 0.00 insulin-like growth X81584 factor bindingprotein 6; Igfbp6 96764_at −2.18 0.00 4.23 4.92 2.47 10.03 UNK_AJ007971AJ007971 110795_at 0.00 0.00 0.00 0.00 −2.27 0.00 JDP1-PENDING AI85244594193_at 0.00 0.00 −3.26 0.00 −3.75 −2.14 KCNA7 AF032099 98787_at 0.000.00 0.00 0.00 0.00 −4.22 potassium inwardly D50581 rectifying channel,subfamily J, member 11; Kcnj11 102849_at 0.00 0.00 −3.01 0.00 0.00 0.00potassium inwardly- D88159 rectifying channel, subfamily J, member 8;Kcnj8 94379_at 0.00 −2.47 −1.93 0.00 −2.35 −2.21 kinesin heavy chainD17577 member 1B; Kif1b 93527_at 0.00 −2.06 −2.23 0.00 0.00 0.00 KLF9Y14296 93528_s_at 0.00 −1.98 0.00 0.00 −2.51 0.00 KLF9 AI848050 94321_at0.00 0.00 0.00 0.00 −2.29 0.00 keratin complex 1, V00830 acidic, gene10; Krt1- 10 97976_at 0.00 0.00 0.00 0.00 −2.24 0.00 kinectin 1; Ktn1L43326 92366_at 0.00 −2.03 0.00 0.00 0.00 0.00 laminin, alpha 2; U12147Lama2 101990_at 0.00 −3.06 −2.70 0.00 −3.72 −1.80 lactate X51905dehydrogenase 2, B chain; Ldh2 96608_at 0.00 0.00 0.00 0.00 −2.42 0.00lupus nephritis- AF023463 associated peptide 1; Lnap1 113140_at 0.000.00 0.00 0.00 −3.11 −2.24 LOC56046 AI846417 103090_at 0.00 0.00 0.000.00 0.00 −2.06 LOC56046 AI838742 99536_at 0.00 0.00 0.00 0.00 −2.79−2.17 UNK_AB016080 AB016080 112850_at 0.00 −1.89 −1.68 0.00 −2.20 −2.12UNK_AW121352 AW121352 101115_at 0.00 0.00 0.00 −2.20 −2.15 −0.12lactotransferrin; Ltf J03298 130772_at 0.00 −2.36 −2.24 0.00 0.00 0.00LYNX1 AI838844 137205_f_at 0.00 0.00 0.00 0.00 −2.71 0.00 LYNX1 AI839851102828_at 0.00 0.00 0.00 0.00 −2.31 −1.54 mitogen activated U39066protein kinase kinase 6; Map2k6 102829_s_at 0.00 0.00 0.00 0.00 −2.060.00 MAP2K6 X97052 102431_at 0.00 0.00 0.00 0.00 −0.45 −2.09 MTAPTM18775 102742_g_at 0.00 0.00 0.00 0.00 −1.89 −2.98 MTAPT M18775 96311_at0.00 −2.37 0.00 0.00 −3.29 −2.09 MBP M11533 97282_at −11.15 0.00 0.000.00 0.00 0.00 MELA D10049 103838_at 0.00 0.00 0.00 0.00 −2.36 −1.98MG29 AB010144 102061_at 0.00 −3.00 −3.32 −3.75 −5.64 −2.29 MLF1 AF100171103622_at −1.34 0.00 0.00 0.00 −2.19 −1.80 UNK_AW050255 AW05025596348_at 0.00 −2.13 0.00 0.00 −2.20 0.00 UNK_AW121217 AW121217 101082_at0.00 0.00 −2.34 0.00 −2.56 −1.12 MOD1 J02652 102096_f_at 0.00 0.00 −2.420.00 0.00 3.13 MUP1 AI255271 101909_f_at 0.00 0.00 −4.14 0.00 0.00 3.70MUP3 M16357 100017_at −1.56 0.00 0.00 0.00 −2.75 0.00 myosin-bindingU68267 protein H; Mybph 97990_at 0.00 0.00 0.00 0.00 −2.28 0.00 myosinheavy chain D85923 11, smooth muscle; Myh11 98616_f_at 0.00 −8.12 −2.13−32.76 −4.63 −4.81 MYHCB AJ223362 93050_at 0.00 −2.77 0.00 0.00 −2.91−2.11 myosin light chain, M91602 phosphorylatable, cardiac ventricles;Mylpc 94122_at 7.47 3.44 2.58 0.00 −3.81 −1.94 MYOC AF041335 92407_at0.00 −1.90 0.00 0.00 −3.23 −2.03 MYOM1 AJ012072 102041_at 0.00 0.00 0.000.00 −2.53 −1.90 MYOM2 AJ001038 92876_at 0.00 0.00 0.00 0.00 −4.44 −2.04NADH AA590675 dehydrogenase (ubiquinone) Fe—S protein 4 (18 kDa); Ndufs493006_at 0.00 0.00 0.00 0.00 −4.91 −2.79 NFIC Y07693 96153_at 0.00 0.00−4.66 −8.35 −10.04 −5.56 neutrophilic granule L37297 protein; Ngp92824_at 0.00 0.00 0.00 0.00 −2.29 −1.91 NM23-M6 AF051942 99009_at 0.00−2.54 0.00 0.00 −2.06 0.00 nicotinamide Z49204 nucleotidetranshydrogenase; Nnt 98365_at 0.00 0.00 0.00 0.00 0.00 −2.02 nitricoxide synthase D14552 1, neuronal; Nos1 102371_at 0.00 0.00 0.00 0.00−3.52 −2.20 nuclear receptor X16995 subfamily 4, group A, member 1;Nr4a1 92362_at 0.00 0.00 0.00 0.00 0.00 −2.83 NTTP1 X95518 99549_at 0.00−3.17 0.00 0.00 3.34 2.12 osteoglycin; Ogn D31951 104479_at 0.00 0.000.00 0.00 −4.22 −5.06 purinergic receptor L14751 P2Y, G-protein coupled2; P2ry2 113762_at 0.00 0.00 0.00 0.00 −2.71 0.00 UNK_AI510151 AI51015196735_at 0.00 0.00 0.00 0.00 0.00 −2.76 UNK_AW049732 AW049732 93308_s_at0.00 0.00 0.00 −1.80 −4.41 0.00 PCX M97957 100489_at 0.00 0.00 0.00 0.000.00 −2.12 phosphodiesterase U68171 7A; Pde7a 115211_at 0.00 0.00 0.000.00 −2.66 −1.52 PDHX AA987055 103526_at 0.00 0.00 0.00 0.00 −3.17 −2.61peptidyl arginine D16580 deiminase, type II; Pdi2 102049_at −1.92 0.000.00 0.00 −2.30 0.00 PDK4 AJ001418 103297_at 0.00 0.00 −5.49 0.00 −5.13−4.79 6-phosphofructo-2- X98848 kinase/fructose-2,6- biphosphatase 1;Pfkfb1 93567_at 0.00 0.00 0.00 0.00 −2.14 −1.90 PFN2 AW122536 92599_at0.00 0.00 0.00 0.00 −2.14 −1.47 PGAM2 AF029843 94733_at 0.00 −1.95 −2.18−1.90 −2.98 −1.72 P glycoprotein 2; J03398 Pgy2 94855_at 0.00 0.00 0.000.00 −4.56 −3.15 prohibitin; Phb X78682 92519_at 0.00 −2.02 −2.13 0.00−2.66 −2.06 phosphorylase X74616 kinase alpha 1; Phka1 97094_at 0.000.00 −2.50 0.00 −5.08 −2.05 phosphorylase J03293 kinase gamma; Phkg107109_at 0.00 0.00 0.00 0.00 −4.21 −2.18 PHRET1 AI835608 104431_at 0.000.00 0.00 0.00 −3.03 −1.83 protein kinase C, D11091 theta; Pkcq 98004_at0.00 0.00 0.00 0.00 −2.53 −2.11 protein kinase M63554 inhibitor, alpha;Pkia 98005_at 0.00 0.00 0.00 0.00 −2.57 −1.86 PKIA AW125442 113154_at0.43 0.00 −2.71 −1.11 −2.08 2.44 UNK_AI854500 AI854500 96114_at 0.000.00 0.00 0.00 −2.25 0.00 UNK_AW122076 AW122076 93933_at 0.00 0.00 0.000.00 −2.41 −2.58 protein phosphatase U89924 1, regulatory (inhibitor)subunit 5; Ppp1r5 97989_at 0.00 0.00 0.00 0.00 −2.59 −1.60 proteinphosphatase M81483 3, catalytic subunit, beta isoform; Ppp3cb 96256_at0.00 0.00 0.00 0.00 −2.17 0.00 peroxiredoxin 3; M28723 Prdx3 97096_at0.00 0.00 0.00 0.00 −5.20 −2.84 protein kinase, J02935 cAMP dependentregulatory, type II alpha; Prkar2a 100595_at 0.00 0.00 0.00 0.00 −2.330.00 PTP4A2 AF035644 101027_s_at 0.00 −1.93 0.00 0.00 −2.20 −1.52 PTTG1AF069051 96720_f_at 0.00 0.00 0.00 0.00 −2.67 0.00 parvalbumin; PvaX59382 104098_at 0.00 −2.59 −2.95 −3.60 −3.43 −2.09 peroxisomal L28835membrane protein 2, 22 kDa; Pxmp2 92410_at 0.00 0.00 0.00 0.00 0.00−2.59 RAD23a homolog X92410 (S. cerevisiae); Rad23a 104680_at 0.00 −2.27−2.19 0.00 0.00 0.00 RAMP1 AJ250489 100562_at 0.00 0.00 0.00 0.00 −3.97−3.48 UNK_AI846319 AI846319 99951_at 0.00 0.00 0.00 0.00 0.00 −4.08 RORCAF019660 98464_at 0.00 0.00 0.00 0.00 −2.35 0.00 UNK_AW124196 AW12419696296_at 0.00 0.00 0.00 0.00 −2.25 0.00 RPML7 AI843685 98007_at 0.00−3.41 −2.82 −3.72 −3.18 −2.45 RPS6KA2 AJ131021 92237_at 0.00 0.00 0.000.00 −9.91 −5.35 retinoid X receptor X66225 gamma; Rxrg 103448_at 0.002.51 −4.75 −1.37 −6.47 3.81 S100 calcium M83218 binding protein A8(calgranulin A); S100a8 103887_at 4.41 0.00 −8.99 −5.52 −6.50 5.43 S100calcium- M83219 binding protein A9 (calgranulin B); S100a9 102763_at0.00 0.00 0.00 0.00 −2.52 −1.62 UNK_AF064748 AF064748 102712_at −3.842.96 4.98 8.61 4.23 0.00 serum amyloid A 3; X03505 Saa3 99665_at 0.000.00 −2.09 −2.05 −3.58 −2.00 special AT-rich U05252 sequence bindingprotein 1; Satb1 111448_f_at 0.00 −1.94 −1.73 0.00 −2.64 −1.81 SATB1AI121993 111449_r_at 0.00 0.00 0.00 0.00 −2.19 0.00 SATB1 AI121993103399_at 0.00 0.00 0.00 0.00 0.00 −2.01 SCML1 AI853225 102808_at 0.000.00 0.00 0.00 −2.21 −1.64 sodium channel, L48687 voltage-gated, type I,beta polypeptide; Scn1b 94140_at 0.48 2.44 −2.79 0.00 0.00 0.00 SCVRM59446 92742_at 0.00 −4.88 0.00 0.00 −2.58 −1.69 SCYA11 U77462 98624_at0.00 −1.98 −2.23 0.00 −2.88 −2.07 seb4 protein; Seb4 X75316 103395_at0.00 0.00 0.00 0.00 −2.03 −1.79 SGCA AF019564 101394_at 0.00 0.00 0.000.00 −2.25 0.00 SGCG AB024922 96204_at 0.00 0.00 0.00 0.00 −2.53 0.00SH3BGR AJ239082 102208_at 0.00 −1.79 −2.13 0.00 −2.43 0.00 ST3GALVIAI153959 99320_at 0.00 0.00 0.00 0.00 −2.62 0.00 sialyltransferase 8X98014 (alpha 2, 8 sialytransferase) E; Siat8e 92722_f_at 0.00 0.00 0.000.00 −2.03 0.00 sine oculis-related X80339 homeobox 1 homolog(Drosophila); Six1 93000_g_at −2.80 −2.40 0.00 0.00 0.00 0.00 SIX4D50416 93001_at −1.65 0.00 0.00 0.00 −2.44 0.00 sine oculis-relatedD50418 homeobox 4 homolog (Drosophila); Six4 102314_at 0.00 −2.97 0.000.00 −4.23 −2.74 solute carrier family M23383 2 (facilitated glucosetransporter), member 4; Slc2a4 109069_at 0.00 −2.82 −2.00 0.00 0.00 3.28SLC39A1 AI255982 96926_at −2.06 −2.87 −2.56 0.00 0.00 0.00 UNK_AA980164AA980164 96042_at 0.00 0.00 0.00 0.00 −2.94 0.00 SOD2 L35528 92302_at0.00 0.00 −1.87 0.00 −2.80 0.00 Son of sevenless Z11664 homolog 2,(Drosophila); Sos2 92726_at 0.00 0.00 0.00 0.00 −3.87 −2.50 SOX6AJ010605 113125_at 0.00 0.00 0.00 0.00 −3.81 −2.03 UNK_AI851671 AI851671100952_at 0.00 0.00 0.00 0.00 −2.38 −2.24 stromal interaction U47323molecule 1; Stim1 92888_s_at 0.00 0.00 0.00 0.00 −2.62 −1.73 proteintyrosine U34973 phosphatase-like unspliced c-terminal product andspliced c-terminal end STYX; hStyxb 93501_f_at 0.00 0.00 0.00 0.00 −2.610.00 SUCLA2 AF058955 93502_r_at 0.00 0.00 0.00 0.00 −4.71 0.00 SUCLA2AF058955 96268_at 0.00 0.00 0.00 0.00 −2.29 0.00 UNK_AI840979 AI840979100587_f_at 0.00 0.00 0.00 0.00 −2.02 0.00 SUPT4H AI843959 93994_at 0.000.00 0.00 0.00 −2.00 0.00 SYCP3 AW212131 102221_at 0.00 0.00 0.00 0.00−2.28 −1.75 SYNGR1 AJ002306 100355_g_at 0.00 0.00 0.00 0.00 −2.24 −1.51TBX14 AF013282 102256_at 0.00 0.00 0.00 0.00 −2.14 0.00 TBX15 AF041822102344_s_at 0.00 −2.14 −2.56 −4.39 −4.38 −2.48 TCEA3 AI132239 97402_at−2.80 −5.83 −4.24 −3.96 −4.97 −2.21 thioether S- M88694methyltransferase; Temt 101964_at 0.00 0.00 −2.16 0.00 0.00 3.47transketolase; Tkt U05809 92224_at 0.00 −5.01 0.00 0.00 0.00 0.00tetranectin X79199 (plasminogen- binding protein); Tna 101063_at 0.00−3.19 0.00 0.00 0.00 −2.68 troponin C, M29793 cardiac/slow skeletal;Tncc 98561_at 0.00 −3.08 0.00 0.00 0.00 −2.24 UNK_AJ242874 AJ24287493532_at 0.00 0.00 0.00 0.00 −2.52 0.00 troponin I, skeletal, J04992fast 2; Tnni2 101383_at 0.00 −2.85 0.00 0.00 −1.69 −1.97 TNNT1 AJ13171199532_at 0.00 0.00 0.00 0.00 −2.17 0.00 transducer of ErbB- D78382 2.1;Tob1 101446_at 0.00 0.00 0.00 0.00 −2.49 0.00 TPD52L1 AF004428 93266_at0.00 −2.33 −1.90 0.00 −2.55 −2.51 tropomyosin 5; U04541 Tpm5 93509_at0.00 0.00 −1.82 0.00 −2.58 −2.00 UBE2B U57690 99507_at 0.00 0.00 −3.440.00 −2.86 −1.60 UCP M21247 93392_at −1.48 −1.66 0.00 0.00 −2.72 −1.67UCP3 AB010742 95537_at 0.00 0.00 0.00 0.00 −2.26 0.00 ULK2 AB01957792820_at 0.00 0.00 0.00 0.00 −2.43 −2.13 USP2 AI846522 92821_at 0.000.00 0.00 0.00 −2.73 −1.71 USP2 AF079565 114088_at 0.00 0.00 0.00 0.00−2.55 −1.55 VAMP1 AI850070 92496_at 0.00 0.00 0.00 0.00 0.00 −2.59 VAMP5AF035643 103001_at 0.00 −2.17 −1.96 0.00 −3.42 −2.12 vascularendothelial U43836 growth factor B; Vegfb 98549_at 0.00 −1.87 0.00 0.00−2.11 0.00 vitronectin; Vtn M77123 115141_at 0.00 0.00 −3.89 0.00 −5.600.00 UNK_AW049840 AW049840 103824_at −1.39 −2.00 −2.01 0.00 −1.92 −1.71WFS1 AF084482 103238_at 0.00 0.00 0.00 0.00 −4.41 0.00 wingless-relatedM89797 MMTV integration site 4; Wnt4 96063_at 0.00 0.00 0.00 0.00 −2.020.00 X-ray repair X66323 complementing defective repair in Chinesehamster cells 5; Xrcc5 99932_at 0.00 0.00 0.00 0.00 0.00 −6.45 ZFP100U14556 101456_at 0.00 0.00 0.00 0.00 −2.16 −1.95 ZFP106 AF060245108046_at 0.00 0.00 0.00 0.00 −2.37 −2.19 ZFP238 AI844802

TABLE 5 BMP-2-induced changes in the expression of known genespreviously associated with bone or cartilage metabolism. Gene TitleSymbol GenBank Day 1 Day 2 Day 3 Day 4 Day 7 Day 14 Cell SurfaceProteins OSTEOBLAST Osf2 D13664 2.1 +/− 0.2 4.1 +/− 0.6 7.4 +/− 0.2 11.6+/− 0.3  64.3 +/− 6.7  42.7 +/− 12   SPECIFIC FACT. 2 MEGAKAR. STIM.Prg4 AB034730 0 +/− 0 5.6 +/− 0.2 4.3 +/− 0.2 4.8 +/− 0.1 0 +/− 0 0 +/−0 FACT. CADHERIN 11 Cdh11 D21253 0 +/− 0 2.1 +/− 0.3 2.9 +/− 0   5.5 +/−3.3 37.9 +/− 9.6  38.2 +/− 7.3  CD44 ANTIGEN Cd44 M27129 0 +/− 0 3.2 +/−0.5 3.9 +/− 0.1 4.3 +/− 0.3 4.5 +/− 0.2   6 +/− 0.6 CADHERIN 2 Cdh2AB008811 0 +/− 0 0 +/− 0 0 +/− 0 2.1 +/− 0.5 15.9 +/− 1.5  14.6 +/− 0.2 SYNDECAN 2 Sdc2 U00674 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.1 +/− 1.2 4.5+/− 0.2 INTEGRIN ALPHA Itgav U14135 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.4+/− 1.4 5.7 +/− 1   V (CD51) NEURAL CELL Ncam X07233 0 +/− 0 0 +/− 0 0+/− 0   4 +/− 1.3 7.8 +/− 1.9 3.4 +/− 0.6 ADHESION MOLECULE SYNDECAN 1Sdc1 X15487 0 +/− 0   2 +/− 0.6 0 +/− 0 0 +/− 0 7.2 +/− 1   6.9 +/− 0.2L-34 Lgals3 X16074 0 +/− 0 1.6 +/− 0.3 2.1 +/− 0.5 2.4 +/− 0.5   6 +/−0.9 8.4 +/− 0.9 GALACTOSIDE- BINDING LECTIN. GAP JUNC. Gja1 X61576 0 +/−0 2.3 +/− 0.5 0 +/− 0   4 +/− 0.8 8.4 +/− 1.9 14.8 +/− 3.6  MEMB. CHANN.PROT. ALPHA 1 INTEGRIN BETA 3 Itgb3 AF026509 0 +/− 0 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 7.2 +/− 1   (CD61) INTEGRIN BETA 2 Itgb2 X14951 2.6 +/−0.6   3 +/− 0.3 2.8 +/− 1.1 2.9 +/− 0.3 2.9 +/− 1.1 8.8 +/− 0.1 (CD18)VASCULAR CELL Vcam1 X67783 0 +/− 0 2.2 +/− 0   0 +/− 0 2.9 +/− 0.6 3.5+/− 0.9 6.8 +/− 1.4 ADHESION MOLECULE 1 Cytokines CONNECTIVE Ctgf M706425.1 +/− 0.8 8 +/− 1 10.2 +/− 3.1  5.8 +/− 1.7 19.1 +/− 3.1  9.6 +/− 0.5TISSUE GROWTH FACTOR STROMAL CELL Sdf5 D50462 2.2 +/− 0.8 4.6 +/− 0.58.3 +/− 2.3 10.2 +/− 3.4  17.5 +/− 1.6  10.1 +/− 1.1  DERIVED FACT. 5MONO. Scya8 AB023418 0 +/− 0 3.9 +/− 1.8   6 +/− 2.3   9 +/− 2.3 9.4 +/−1.3 4.8 +/− 2   CHEMOATTRAC. PROT.-2 PRECUR. SMALL INDUCIB. Scya2 J044673.3 +/− 0.6 7.4 +/− 1.4 8.5 +/− 1.9 8.4 +/− 0.6 5.9 +/− 0.9 1.9 +/− 1  CYTOKINE A2 IL-1 BETA Il1b M15131 1.1 +/− 1.9 5.4 +/− 2   4.4 +/− 2.14.3 +/− 1.1 0 +/− 0 5.4 +/− 0.9 CYSTEINE Cyr61 M32490 1.7 +/− 0.5 2.6+/− 0.3 5.2 +/− 0.3 7.8 +/− 2.3 6.4 +/− 1.8 2.8 +/− 0.7 RICH PROT. 61TGF, BETA 1 Tgfb1 M13177 0 +/− 0 2.6 +/− 0.5 0 +/− 0 2.9 +/− 0.7 11.3+/− 0.8  7.6 +/− 0.7 MIDKINE Mdk M35833 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 022.2 +/− 1.8  10.9 +/− 1.5  INHIBIN BETA-A Inhba X69619 0 +/− 0 1.5 +/−0.4   2 +/− 0.7 4.9 +/− 4.4 5.2 +/− 2.8 0 +/− 0 WNT1 INDUCIB. Wisp2AF126063 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.3 +/− 0.3 SIG.PATHWAY PROT. 2 STROMAL CELL Sdf1 D43805 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 00 +/− 0 6.7 +/− 1   DERIVED FACT. 1 COLONY STIM. Csf1 M21149 2.8 +/− 0.63 +/− 1 1.9 +/− 0.1 0 +/− 0 3.1 +/− 0.7 5.3 +/− 0.7 FACT. 1 (MACROPHAGE)PDGF, ALPHA Pdgfa M29464 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 5.7 +/− 1.4 0+/− 0 TGF, BETA 3 Tgfb3 M32745 0 +/− 0 0 +/− 0 0 +/− 0 2.6 +/− 0.3 4.1+/− 1.3 1.9 +/− 0.3 BONE Bmp8a M97017 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0+/− 0 5.6 +/− 1.2 MORPHO- GENETIC PROT. 8A TPA REPRESSED TPAR1 S74318−1.8 +/− 0.1   0 +/− 0 0 +/− 0 0 +/− 0 2.2 +/− 0.2   9 +/− 1.9 GENE 1SECRETED Sfrp3 U91905 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 9.5 +/− 1   2.2+/− 0.8 FRIZZLED- RELATED PROT. 3 OSTEO- Tnfrsf11b U94331 0 +/− 0 0 +/−0 0 +/− 0 0 +/− 0 5.2 +/− 0.6 0 +/− 0 PROTEGERIN FOLLISTATIN Fst Z295320 +/− 0 2.4 +/− 0.3 0 +/− 0 0 +/− 0 4.2 +/− 0.1 0 +/− 0 GROWTH Gdf1M62301 0 +/− 0 0 +/− 0 0 +/− 0 −4.7 +/− 0   0 +/− 0 0 +/− 0 DIFFEREN.FACT. 1 Extracellular Matrix Proteins TENASCIN C Tnc X56304 0 +/− 0 6.6+/− 1.6 14.4 +/− 1.7  34.5 +/− 13   91.6 +/− 22.

68.9 +/− 7.6  SECRETED Spp1 J04806 2.4 +/− 0.9 3.4 +/− 1.4 6 +/− 1 15.7+/− 10.

46.2 +/− 8.7  98.3 +/− 5.1  PHOSPHOPROT. 1 BIGLYCAN Bgn X53928 1.8 +/−0.3 2.8 +/− 0.5 4.2 +/− 0.1 5.8 +/− 1   11.6 +/− 1.3  12.1 +/− 1.4 PROCOLL., Col5a1 AB009993 0 +/− 0 0 +/− 0 3.1 +/− 0.9   9 +/− 2.2 17.1+/− 3.2  15.5 +/− 1.5  TYPE V, ALPHA 1 CHONDROITIN Cspg2 D16263 2.4 +/−1   3.1 +/− 0.6 4.4 +/− 0.5 5.4 +/− 0.4 5.1 +/− 1.2 2.4 +/− 0.3 SULFATEPROTEOGLYCAN 2 PROCOLL., Col5a2 L02918 0 +/− 0 2.4 +/− 0.3 3.6 +/− 0.5 7+/− 0 17.2 +/− 1  18.3 +/− 0.4  TYPE V, ALPHA 2 AGGRECAN Agc L07049 0+/− 0 0 +/− 0 0 +/− 0 4.8 +/− 2   27.6 +/− 3.4  4.7 +/− 0.8 FIBRONECTIN1 Fn1 M18194 0 +/− 0 3.1 +/− 0.2   3 +/− 0.4 4.5 +/− 0.4 7.8 +/− 0.5 6.1+/− 0.4 ALPHA-1 TYPE-III Col3a1 M18933 0 +/− 0 2.3 +/− 0.3 2.2 +/− 0.3  5 +/− 0.2  13 +/− 1.2 7.9 +/− 0.7 COLLAGEN. THROM- Thbs1 M87276   3+/− 0.7 3.8 +/− 0.8 3.9 +/− 1.2 9.5 +/− 3.4 27.2 +/− 6.4  8.5 +/− 2  BOSPONDIN 1 PROCOLL., Col12a1 U25652 0.5 +/− 1.4   2 +/− 0.3 3.9 +/− 0.47.9 +/− 2.5 29.4 +/− 7.5  12.1 +/− 1.3  TYPE XII, ALPHA 1 PROCOLL.,Col6a2 X65582 0 +/− 0 0 +/− 0 0 +/− 0 5.6 +/− 0   14.1 +/− 2.6  9.7 +/−0.5 TYPE VI, ALPHA 2 COL8A1 col8a1 X66977 0 +/− 0 2.4 +/− 0.2 1.8 +/−0.1 6.8 +/− 1.4 23.4 +/− 3.7  8.1 +/− 3.1 LUMICAN Lum AF013262 0 +/− 0 0+/− 0 0 +/− 0 2.9 +/− 0.5 8.5 +/− 0.8 7.7 +/− 1   COL11A2 Col11a2AF100956 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 23.7 +/− 0.2  24.2 +/− 9  PROCOLL., Col11a1 D38162 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 79.8 +/− 1.6 49.7 +/− 3.7  TYPE XI, ALPHA 1 INTEGRIN Ibsp L20232 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 237.8 +/− 9    174.1 +/− 17   BINDING SIALOPROT. BONE GLA.Bglap1 L24431 0 +/− 0 0 +/− 0 −4.1 +/− 1   0 +/− 0 14.9 +/− 4.7  59.6+/− 3.8  PROT. 1 PROCOLL., Col2a1 M65161 0 +/− 0 0 +/− 0 −1.8 +/− 0.1  0 +/− 0 168.1 +/− 24   28.9 +/− 3   TYPE II, ALPHA 1 PROCOLL., Col6a1Z18271 0 +/− 0 0 +/− 0 1.7 +/− 0   3.4 +/− 0.1   5 +/− 0.3   4 +/− 0.4TYPE VI, ALPHA 1 PROCOLL., Col10a1 Z21610 0 +/− 0 0 +/− 0 0 +/− 0 0 +/−0 45.1 +/− 29.

5.6 +/− 3.2 TYPE X, ALPHA 1 CARTILAGE Comp AF033530 0 +/− 0 2.2 +/− 0.40 +/− 0 2.3 +/− 0.6 10.8 +/− 0.7  2.8 +/− 0.4 OLIGOMERIC MATRIX PROT.CARTILAGE Crtl1 AF098460 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 14.9 +/− 1.1  0+/− 0 LINK PROT. 1 PROCOLL., Col14a1 AJ131395 0 +/− 0 0 +/− 0 0 +/− 0 0+/− 0 4.1 +/− 0.8 2.1 +/− 0.3 TYPE XIV, ALPHA 1 PROCOLL., Col9a1 D175110 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0  14 +/− 0.7 0 +/− 0 TYPE IX, ALPHA 1PROCOLL., Col15a1 D17546 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 6.9 +/− 0.6 3.9+/− 0.7 TYPE XV BONE GLA. Bglap-rs1 L24430 0 +/− 0 0 +/− 0 0 +/− 0 0 +/−0 0 +/− 0 77.8 +/− 18.

PROT., RELATED SEQ. 1 EXTRA- Ecm1 L33416 0 +/− 0 2.4 +/− 0.2 2.6 +/− 0.2  3 +− 0.4 3.2 +/− 0.6 5.1 +/− 0.2 CELLULAR MATRIX PROT. 1 ELASTIN ElnU08210 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.2 +/− 1.8 ALPHA 3 TYPEIX Col9a3 X91012 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 9.8 +/− 0.8 0 +/− 0COLLAGEN PROCOLL., Col9a2 Z22923 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.4 +/−2.1 0 +/− 0 TYPE IX, ALPHA 2 Extracellular Proteins NEURO Nbl1 D50263 0+/− 0 0 +/− 0 0 +/− 0 0 +/− 0 6 +/− 3.7 5.5 +/− 1.1 BLASTOMA. SUPP. OFTUMORIGEN. 1 IGF Igfbp4 X76066 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 7.1 +/−1.2 5.4 +/− 0.4 BINDING PROT. 4 APOLIPOPROT. E Apoe D00466 0 +/− 0 1.8+/− 0.4 2.4 +/− 0.1 2.7 +/− 0.1 3.8 +/− 0.2 4.8 +/− 0.3 IGF Igfbp3X81581 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   5 +− 0.4 3.2 +/− 1   BINDINGPROT. 3 VITRONECTIN Vtn M77123 −2.1 +/− 0.2 −4.2 +/− 1   −2.3 +/− 0.3  0 +/− 0 0 +/− 0 0 +/− 0 Intracellular Proteins CELL DIV. Cdc2a M387241.6 +/− 0.6 7.2 +/− 1.1 10.6 +/− 0.9  13.4 +/− 3.9  12.1 +/− 1.6    4+/− 0.2 CYCLE 2 HOMOLOG A LYSYL OXIDASE Lox M65142 0 +/− 0 5.3 +/− 0.78.9 +/− 1   12.6 +/− 0.6  22.8 +/− 1.3  15.5 +/− 0.9  PROCOLL-LYS.,Plod2 AF080572 0 +/− 0 2.9 +/− 0.4 6.2 +/− 2.6 15.2 +/− 4.4  13.5 +/−1.8  11.6 +/− 1.7  2-OXOGLUT.5- DIOXYGEN. 2 ALK. Akp2 J02980 0 +/− 0 0+/− 0 5 +/− 1 6.1 +/− 3.6 32.6 +/− 2.9  18.5 +/− 3.8  PHOSPHATASE 2,LIVER HEME Hmox1 X13356 1.9 +/− 0.3   4 +/− 1.5 4.5 +/− 1.2 7.3 +/− 2.38.2 +/− 0.3 7.6 +/− 1   OXYGENASE (DECYCLING) 1 PROCOLL-LYS., Plod3AF046783 0 +/− 0 3.7 +/− 0.6 4.6 +/− 0.2 5.1 +/− 0.5 8.5 +/− 0.7 3.8 +/−0.9 2-OXOGLUT. 5-DIOXYGEN. 3 PHOSPHOLIPASE Pla2g4 M72394 0 +/− 0 2.6 +/−0.5 3.9 +/− 0.1 6.9 +/− 1.8 7.2 +/− 0.6 4.4 +/− 0.1 A2, GROUP 4 ATPASE,H+ Tclrg1 AB022322 0 +/− 0 0 +/− 0 3.1 +/− 0.8 0 +/− 0   7 +/− 1.4 27.8+/− 2.4  TRANSPORTING, LYSOSOMAL I LYSYL Loxl2 AF117951 0 +/− 0 0 +/− 00 +/− 0 7.2 +/− 0.6 7.7 +/− 0.8 2.1 +/− 0.4 OXIDASE-LIKE PROT. 2PROSTAGLAN.- Ptgs2 M64291 0 +/− 0 2.5 +/− 0.3 2.3 +/− 0   8.9 +/− 3.45.5 +/− 1.2 −0.3 +/− 1.6   ENDOPEROX. SYNTHASE 2 CREATINE Ckb M74149 0+/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.6 +/− 0.6 28.6 +/− 2   KINASE, BRAINCALRETICULIN Calr X14926 0 +/− 0 2.9 +/− 0.2   3 +/− 0.3 4.1 +/− 0.6 5.5+/− 0.2 3.9 +/− 0.3 BCL2- Bax L22472 0 +/− 0 2.5 +/− 0.4 2.1 +/− 0.2 0+/− 0 4.9 +/− 0.8 0 +/− 0 ASSOCIATED X PROT. CARBONIC Car2 M81022 0 +/−0 0 +/− 0 0 +/− 0 0 +/− 0 0.3 +/− 1.4 13.8 +/− 3.7  ANHYDRASE 2 LYSYLOXIDASE- Loxl U79144 0 +/− 0   2 +/− 0.1 0 +/− 0 3.5 +/− 0.1 4.6 +/− 0.63.4 +/− 0.3 LIKE FATTY ACID Fasn X13135 0 +/− 0 −1.5 +/− 2.6   −4.4 +/−0.6   −3.3 +/− 2.4   −3.9 +/− 1.2   −0.2 +/− 2.3   SYNTHASE ProteasesTISSUE INHIB. Timp M17243 1.1 +/− 2   12.8 +/− 3.2  25.4 +/− 7.6  48.1+/− 11.

100.3 +/− 11    56 +/− 3.5 OF METALLOPROT. SERINE Spi2-2 M64086 0 +/− 06.8 +/− 1.2 7.4 +/− 0.8 8.3 +/− 2.5 7.7 +/− 1.3 2.4 +/− 1.1 PROTEASEINHIB. 2-2 BONE Bmp1 L24755 0 +/− 0 0 +/− 0 2.9 +/− 0.5 6.8 +/− 1.7  23+/− 4.1 18.1 +/− 0.3  MORPHO- GENETIC PROT. 1 MATRIX Mmp14 U54984 0 +/−0 2.8 +/− 0.4 2.7 +/− 0     7 +/− 1.3 23.1 +/− 3.8  18.1 +/− 4.6 METALLOPROT. 14 CATHEPSIN K Ctsk X94444 0 +/− 0 0 +/− 0 0 +/− 0 6.1 +/−4   11.3 +/− 3.1  47 +/− 1.6 MATRIX Mmp9 Z27231 0 +/− 0 0 +/− 0 0 +/− 0  20 +/− 16.8 16.3 +/− 12.

221.5 +/− 18   METALLOPROT. 9 PROCOLL. Pcolce AB008548 0 +/− 0 0 +/− 0 0+/− 0 3.3 +/− 0.5   7 +/− 1.2 6.7 +/− 0.8 C-PROT. ENHANCER PROT.PLASMINOGEN Plat J03520 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 5.3 +/− 1.3 4.6+/− 0.6 ACT., TISSUE MATRIX Mmp2 M84324 −2.1 +/− 0.3   −1.8 +/− 0.1  0.1 +/− 1.7 2.7 +/− 0.4 8.1 +/− 1.1 7.2 +/− 0.6 METALLOPROT. 2 UROKINASEPlaur X62700 1.7 +/− 0.3 3.1 +/− 0.5 0 +/− 0 4.4 +/− 1   7.8 +/− 0.7 2.3+/− 0.4 PLASMINOGEN ACT. RECEPT. MATRIX Mmp13 X66473 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 19.3 +/− 2.5 144.8 +/− 24   METALLOPROT. 13 PLASMINOGENSerpine1 M33960 0 +/− 0 2.9 +/− 0.7 2.8 +/− 0.3   5 +/− 1.3 3.2 +/− 0.50 +/− 0 ACT. INHIB., TYPE I TISSUE INHIB. OF Timp2 X62622 0 +/− 0 1.7+/− 0.1 1.8 +/− 0   2.6 +/− 0.4 4.7 +/− 0.9 3.8 +/− 0.5 METALLOPROT. 2Receptors TGF BETA Tgfbi L19932 2.8 +/− 0.7 6 +/− 2 5.6 +/− 0.7 7.8 +/−0.7 5.3 +/− 1     2 +/− 0.4 INDUCED, 68 KDA PARATHYROID Pthr X78936 0+/− 0 0 +/− 0   3 +/− 0.1   6 +/− 1.9 57.4 +/− 1.3  25.5 +/− 1.1 HORMONE RECEPT. PTP, RECEPT. Ptprd D13903 0 +/− 0 0 +/− 0 0 +/− 0 1.6+/− 0.1 6.6 +/− 0.4 8.7 +/− 2.2 TYPE, D IL-4 RECEPT., Il4ra M29854 0 +/−0 4.8 +/− 1.4 2.9 +/− 0.1 0 +/− 0 8.1 +/− 0.7 0 +/− 0 ALPHA FIBROBL.Fgfr2 M86441 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 15.3 +/− 2.5  7.9 +/− 1.3GROWTH FACT. RECEPT. 2 COLONY STIM. Csf1r X68932 1.8 +/− 0.5 3.2 +/− 0.43.3 +/− 0.5 4.1 +/− 0.6 3.5 +/− 0.6 10.9 +/− 0.9  FACT. 1 RECEPT.ACTIVIN A Acvr1 L15436 0 +/− 0 0 +/− 0 1.9 +/− 0.2 2.7 +/− 0.3 4.6 +/−0.1 0 +/− 0 RECEPT., TYPE 1 COLONY STIM. Csf3r M58288 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 0 +/− 0 4.9 +/− 0.9 FACT. 3 RECEPT. COLONY STIM. Csf2raM85078 0 +/− 0 2.6 +/− 0.7 3.3 +/− 0.3 0 +/− 0 4.8 +/− 0.8 3.9 +/− 0.4FACT. 2 RECEPT., ALPHA TGF BETA Tgfbr2 S69114 0 +/− 0 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 4.7 +/− 1   RECEPT. II Signal Transduction C-SRC TYROSINECsk U05247 0 +/− 0 2.6 +/− 0.3 0 +/− 0 2.9 +/− 0.1 4.9 +/− 0.4 3.6 +/−0.2 KINASE Transcription Factors MAD Madh6 AF010133 6.7 +/− 3   8.1 +/−1.7 9.9 +/− 2.3 4.6 +/− 0.9 7.7 +/− 2.9 5.5 +/− 0.5 HOMOLOG 6 INHIB. OFIdb1 M31885 3.6 +/− 0.7 8.1 +/− 1.9 7.6 +/− 0.8 4.9 +/− 1.9 4.4 +/− 1.74.9 +/− 0.6 DNA BINDING 1 INHIB. OF DNA Idb2 M69293 2.4 +/− 0.6 4.5 +/−0.6 5.7 +/− 1.4 4.8 +/− 0.5 11.9 +/− 3.2  5.7 +/− 0.7 BINDING 2 RUNTRELATED Runx2 D14636 0 +/− 0 2.6 +/− 0.5 3.8 +/− 0.2 8.9 +/− 2.7 15.8+/− 1.3  20.1 +/− 4.9  TRANSCRIP. FACT. 2 JUN-B Junb J03236 0.9 +/− 1.74.4 +/− 0.5 2.7 +/− 0   3.6 +/− 1.2 5.1 +/− 1   2.3 +/− 0.4 ONCOGENESCLERAXIS Scx S78079 0 +/− 0 3.8 +/− 1.9 6.9 +/− 3.8 0 +/− 0 19.4 +/−6   0 +/− 0 SIG. TRANS. Stat1 U06924 0 +/− 0 2.2 +/− 0.3 3.5 +/− 0.9 4.7+/− 0.3 2.7 +/− 0.1 5.2 +/− 3.2 AND ACT. OF TRANSCRIP. 1 DISTAL-LESSDlx5 U67840 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 8.5 +/− 1   7.5 +/− 1  HOMEOBOX 5 NUC. FACT. Nfatc1 AF049606 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 02.7 +/− 0.8 5.2 +/− 0.8 ACTIV. T-CELLS, CYTOPLAS. 1 MAD Madh2 U60530 0+/− 0   2 +/− 0.3 2.5 +/− 0.2 0 +/− 0 4.5 +/− 0.7 0 +/− 0 HOMOLOG 2 SLUGSlugh U79550 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.4 +/− 3.1 0 +/− 0 INHIB.OF DNA Idb4 X75018 2.8 +/− 1.4 3.5 +/− 0.6 3.7 +/− 1.2 0 +/− 0 1.7 +/−0.2   6 +/− 0.3 BINDING 4

indicates data missing or illegible when filed

TABLE 6 BMP-2-Induced changes in the expression of known genes notexplicitly associated with bone or cartilage metabolism*. Gene TitleSymbol GenBank Day 1 Day 2 Day 3 Day 4 Day 7 Day 14 Cell SurfaceProteins CD68 ANTIGEN Cd68 X68273 2.2 +/− 0.5 3.2 +/− 0.5 3.8 +/− 0.65.1 +/− 0.6 6.5 +/− 1.1 15.8 +/− 0.5  FIBROBL. ACTIVATION Fap Y10007 0+/− 0 0 +/− 0 0 +/− 0 2.3 +/− 0.1 5.6 +/− 0.7 10.9 +/− 0.4  PROT. CD9ANTIGEN Cd9 L08115 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 3.5 +/− 0.3 4.1 +/−0.1 HEPATIC LIPASE Lipc X58426 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 04.5 +/− 0.9 SELECTIN, PLATELET Selpl X91144 0 +/− 0 2.3 +/− 0.2 2.5 +/−0.3 3.2 +/− 0.4 3.2 +/− 0.3 7.2 +/− 0.6 (P-SELECTIN) LIGAND EPHRIN B1Efnb1 Z48781 0 +/− 0 0 +/− 0 1.6 +/− 0.1 0 +/− 0 5.9 +/− 1   3.4 +/− 1.2Cytokines MONO. CHEMOTACTIC Scya7 S71251 4.1 +/− 0.7 9.3 +/− 1.7 5.7 +/−2.3 8.1 +/− 2.2 6.6 +/− 1.5 0 +/− 0 PROT.-3 SMALL INDUCIB. Scya12 U507121.9 +/− 0.1 4.1 +/− 2.1 5.6 +/− 0.8 3.8 +/− 0.1 10.7 +/− 2   0 +/− 0CYTOKINE A12 SECRETED FRIZZLED- Sfrp1 U88566 0 +/− 0 2.8 +/− 0.9 5.9 +/−0.5 11.4 +/− 5.9  9.3 +/− 1.8 2.5 +/− 0.5 RELATED PROT. 1 SMALL INDUCIB.Scyb9 M34815 0 +/− 0 0 +/− 0 3.4 +/− 0.5 5.2 +/− 0.4 3.6 +/− 0.6   7 +/−7.7 CYTOKINE B MEMBER 9 VASCULAR Vegfb U48800 0 +/− 0 −2.3 +/− 1  0 +/−0 −9.6 +/− 9.3   −7.8 +/− 3.9   −2.7 +/− 0.4   ENDOTHELIAL GROWTH FACT.B SMALL INDUCIB. Scya11 U40672 −4.1 +/− 2  −3.4 +/− 0.4   0 +/− 0 −1.5+/− 0.3   −2.6 +/− 1  −2.4 +/− 0.5   CYTOKINE A11 Extracellular ProteinsLIPOCORTIN 1 Anxa1 M24554   2 +/− 0.5 2.4 +/− 0.2 2.7 +/− 0.6 3.8 +/−0.6 4.5 +/− 0.8   5 +/− 0.2 SECRETED FRIZZLED- Sfrp4 AF117709 0 +/− 0−1.3 +/− 0.1   0 +/− 0 0 +/− 0 0 +/− 0 12.7 +/− 0.8  RELATED PROT. 4SUPEROX. Sod3 D50856 0 +/− 0   4 +/− 1.1 3.8 +/− 0.1 3.6 +/− 1   4.4 +/−0.8 0 +/− 0 DISMUTASE 3, EXTRACELL. ANNEXIN A4 Anxa4 U72941 0 +/− 0   1+/− 1.8 2.1 +/− 0.2 2.9 +/− 0.4 3.8 +/− 0.9 4.2 +/− 0.1 AMYLOID BETA(A4) App U84012 0 +/− 0 1.8 +/− 0.2 1.6 +/− 0.2 2.5 +/− 0     4 +/− 0.62.7 +/− 0.4 PRECUR. PROT. Intracellular Proteins PLASTIN2, L Pls2 D378370 +/− 0 4.5 +/− 0.8 4.3 +/− 0.4 5.2 +/− 0.3 8.1 +/− 0.9 11.4 +/− 1.1 CYSTEINE-RICH Csrp2 AF037208 0 +/− 0 3.8 +/− 0.3 8.4 +/− 1.9 15.8 +/−3.4  25.8 +/− 7.5  6.5 +/− 0.8 PROT. 2 FGF REGULATED PROT. Fgfrp U042040 +/− 0 3.7 +/− 0.7   4 +/− 0.9 5.7 +/− 1.4 5.6 +/− 0.7 5.9 +/− 0.8CARBONYL Cbr2 D26123 1.6 +/− 0.4 4.6 +/− 0.4 6.8 +/− 0.5 5.1 +/− 0.2 2.1+/− 0.1 1.9 +/− 0.2 REDUCTASE 2 ENDOPLASMIC Grp58 M73329 0 +/− 0 2.8 +/−0.2 2.8 +/− 0.3 4.8 +/− 0.8   7 +/− 1.6 4.3 +/− 0.3 RETICULUM PROT.CYCLIN D1 Cyl-1 S78355 0 +/− 0 3.2 +/− 0.1 4.5 +/− 0.2 0 +/− 0 7.2 +/−0.6 6.4 +/− 0.6 TRANSPORTER 1, ATP Abcb2 U60019 0 +/− 0 1.8 +/− 0.4 4.2+/− 0.2 3.7 +/− 0.9 4.9 +/− 0.2 5.3 +/− 2.9 BINDING CASSETTE 2′-5′OLIGOADENYLATE Oas1a X04958 1.8 +/− 0.2 2.8 +/− 0.6 4.3 +/− 0.7 5.8 +/−1.2 5.1 +/− 0.4 3.7 +/− 0.5 SYNTHETASE 1A CALCIUM BIND. PROT. S100a10M16465 1.9 +/− 0.5 2.5 +/− 0.1 2.8 +/− 0.5 3.4 +/− 0.2 4.4 +/− 0.7 4.2+/− 0.3 A11 (CALGIZZARIN) MYOSIN LIGHT CHAIN, Myla M19436 0 +/− 0 0 +/−0 0 +/− 0 0 +/− 0   8 +/− 2.5 5.5 +/− 1.1 ALKALI, ATRIA RETINOL BINDINGRbp1 X60387 0 +/− 0 0 +/− 0 0 +/− 0 4.1 +/− 0.9 7.1 +/− 0.8 2.4 +/− 0.1PROT. 1, CELLULAR CYCLIN A2 Ccna2 Z26580 0 +/− 0 3.1 +/− 0.5 3.6 +/− 0.74.8 +/− 0.3 5.7 +/− 0.3 1.9 +/− 0.2 PROCOLL-LYS., Plod1 AF046782 0 +/− 00 +/− 0 0 +/− 0 0 +/− 0 5.2 +/− 1.1 3.4 +/− 0.4 2-OXOGLUT. 5-DIOXYGEN. 1GALACTOSYL- B4galt1 J03880 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   8 +/− 1.8 0+/− 0 TRANSFERASE, POLYPEP. 1 RHO, GDP Arhgdib L07918 0 +/− 0   4 +/−0.4 3.1 +/− 0.3 3.3 +/− 0.5 4.4 +/− 0.3 3.8 +/− 1.2 DISSOCIATION INHIB.BETA STEROL O- Soat1 L42293 0 +/− 0 2.5 +/− 0.6 2.2 +/− 0.2 3.6 +/− 0.25.4 +/− 0.9 2.9 +/− 0.7 ACYLTRANSFERASE 1 CYCLIN D2 Ccnd2 M83749 0 +/− 00 +/− 0 0 +/− 0 0 +/− 0 4.2 +/− 0.1 3.7 +/− 0.1 RAT PROTEASOME Psmb9S59862 0 +/− 0 2.8 +/− 0.6 3.3 +/− 0.4 5.5 +/− 0.9 0 +/− 0 3.8 +/− 4.1HOMOLOG LYMPHOCYTE Lcp2 U20159 0 +/− 0 2.4 +/− 0.4 2.5 +/− 0.3 3.1 +/−0.7 3.2 +/− 0.6 4.8 +/− 0.2 CYTOSOLIC PROT. 2 TRANSPORTER 2, ATP Abcb3U60087 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.7 +/− 2.1 BINDINGCASSETTE CAPPING PROT., Capg X54511 0 +/− 0 2.6 +/− 0.2 2.6 +/− 0.4   3+/− 0.1 3.8 +/− 0.4 4.7 +/− 1   GELSOLIN-LIKE CYCLIN B1, Ccnb1-rs1X58708 0 +/− 0 2.4 +/− 0.2 3.1 +/− 0.2 3.9 +/− 0.4 4.1 +/− 0.1 1.7 +/−0.2 RELATED SEQ. 1 CYCLIN B2 Ccnb2 X66032 0 +/− 0 3.6 +/− 0.5 2.7 +/−0.6 4.4 +/− 0.7 2.9 +/− 0.2 2.2 +/− 0.4 HISTONE Hdac1 X98207 0 +/− 0 0+/− 0 3.2 +/− 0.2 0 +/− 0 7.3 +/− 0.7 3.2 +/− 0.3 DEACETYLASE 1Proteases MATRIX Mmp23 AF085742 0 +/− 0 0 +/− 0 0 +/− 0 11.2 +/− 1  39.9 +/− 3   15.7 +/− 0.6  METALLOPROT. 23 CASPASE 6 Casp6 Y13087 0 +/−0 0 +/− 0 2.8 +/− 1.3 4.9 +/− 2.1 7.6 +/− 1.6 7.7 +/− 0.9 CATHEPSIN HCtsh U06119 0 +/− 0 2.1 +/− 0.4 2.3 +/− 0.2 3.6 +/− 0.2 5.8 +/− 0.8 4.4+/− 0.6 CATHEPSIN S Ctss AF038546 1.8 +/− 0.3 2.8 +/− 0.5 3.2 +/− 0.4 4+/− 0 3.8 +/− 0.5 5.4 +/− 1   PROTEOSOME Psmb8 U22032 0 +/− 0 2.9 +/−0.4 3.5 +/− 0.2 3.7 +/− 0.6 3.4 +/− 0.3 6.3 +/− 4.3 SUBUNIT, BETA TYPE 8SERINE PROTEASE Serpine2 X70296 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 3.4 +/−0.3 8.9 +/− 1.2 INHIB. 4 Receptors IL-2 RECEPT., Il2rg L20048 0 +/− 03.9 +/− 0.7 4.7 +/− 0.2 5.6 +/− 0.5 7.9 +/− 0.8 5.3 +/− 0.9 GAMMA CHAINCYTOKINE RECEPT.- Crlf1 A8040038   3 +/− 1.1 7.6 +/− 1   7.2 +/− 2.914.7 +/− 6.4  8.8 +/− 4   2.1 +/− 0.5 LIKE FACT. 1 FC RECEPT., IGG,Fcgr1 X70980 2.7 +/− 0.5 7.6 +/− 2.7 7.3 +/− 0.6 6.7 +/− 1.2 4.8 +/− 1.10 +/− 0 HIGH AFFINITY I PTP, RECEPT. TYPE, C Ptprc M14342 2.5 +/− 0.53.4 +/− 0.4 4.3 +/− 1.7 5.2 +/− 0.9 3.3 +/− 0.8 6.8 +/− 0.8 CHEMOKINE(C-C) Cmkbr2 U51717 2.9 +/− 1   6.1 +/− 0.8 5.1 +/− 1.3 4.2 +/− 0.4 3.4+/− 0.6 3.6 +/− 0.4 RECEPT. 2 TNF RECEPT. Tnfrsf1a L26349 1.4 +/− 0.32.7 +/− 0.2 1.9 +/− 0   2.8 +/− 0.1 4.1 +/− 0.2   4 +/− 0.1 SUPERFAMILY,MEMBER 1A CHEMOKINE (C-C) Cmkbr1 U29678 3.4 +/− 1.6 4.9 +/− 1   2.4 +/−0.7 2.8 +/− 0.2 1.9 +/− 0.2 13.3 +/− 0.6  RECEPT. 1 PDGF RECEPT., BETAPdgfrb X04367 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.6 +/− 1.5 4.8 +/− 1  POLYPEPTIDE PTP, RECEPT. TYPE. S Ptprs X82288 0 +/− 0 0 +/− 0 0 +/− 0 0+/− 0 4.1 +/− 0.7 5.4 +/− 0.5 FRIZZLED-1 Fzd1 AF054623 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 5 +/− 1 1.4 +/− 0.4 ANGIOTENSIN RECEPT.- Agtrl1 AJ007612 0+/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.2 +/− 0.6 2.9 +/− 0.1 LIKE 1 LEUKEMIAINHIB.Y Lifr D17444 0 +/− 0 1.2 +/− 0.1 0 +/− 0 0 +/− 0 3.2 +/− 0.3 9.9+/− 1.3 FACT. RECEPT. FC RECEPT., IGG. LOW Fcgr3 M14215 0 +/− 0 3.6 +/−0.4 3.4 +/− 0.3 3.6 +/− 0   4.2 +/− 0.4 0 +/− 0 AFFINITY III PTP,RECEPT. TYPE, A Ptpra M36033 0 +/− 0 0 +/− 0 0 +/− 0 2.9 +/− 0.1 3.9 +/−0.7   4 +/− 0.4 CHEMOKINE Cmkbr5 U47036 2.7 +/− 1   4.8 +/− 1.9 2.6 +/−0.1 3.5 +/− 0.2 3.2 +/− 0.2 1.5 +/− 0.2 (C-C) RECEPT. 5 EPH RECEPT. A2Epha2 X76010 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 5.1 +/− 0.9   3 +/− 0.2 EPHRECEPT. B3 Ephb3 Z49086 0 +/− 0 0 +/− 0 0 +/− 0 2.5 +/− 1   7.1 +/− 1.52.9 +/− 0.2 RETINOID X Rxrg X66225 0 +/− 0 0 +/− 0 0 +/− 0 −4.2 +/−3.1   −4.5 +/− 0.4   −4.6 +/− 2.5   RECEPT. GAMMA Signal TransductionAPLYSIA RAS-RELATED Arhc X80638 0 +/− 0 0 +/− 0 3.5 +/− 0.4 5.7 +/− 0.3  7 +/− 0.8 7.6 +/− 0.2 HOMOLOG 9 FYN PROTO-ONCOGENE Fyn M27266 0 +/− 00 +/− 0 1.5 +/− 0.4 2.2 +/− 0.1 4.2 +/− 0.5 4.4 +/− 0.7 RAS P21 PROT.ACT. 3 Rasa3 U20238 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.4 +/− 0.4 4.7 +/−0.5 DOWNSTREAM OF Dok1 U78818 0 +/− 0 1.7 +/− 0.5 2.7 +/− 1.1 4.5 +/−1.4 5.4 +/− 1.5 3.3 +/− 0.1 TYROSINE KINASE 1 MITOGEN-ACTIVATED Map4k4U88984 0 +/− 0 2 +/− 0.3 2.6 +/− 0.3 3.1 +/− 0.1 5.2 +/− 0.5 4.9 +/− 0.7PROT. (KINASE) 4 VAV ONCOGENE Vav X64361 0 +/− 0 4.3 +/− 0.4 3.2 +/− 0.2  4 +/− 0.4 2.3 +/− 0.2 0 +/− 0 HEMATO. CELL Hcls1 X84797 2.7 +/− 1.35.6 +/− 1.5 4.2 +/− 1.3 3.2 +/− 0.6   4 +/− 0.9 3.1 +/− 0.5 SPECIFIC LYNSUBSTR. 1 REGULATOR OF Rgs2 AF215688 0 +/− 0 1.5 +/− 0.4 2.9 +/− 0.9 3.2+/− 0.2 2.8 +/− 0.6 5.6 +/− 0.7 G-PROT. SIG. 2 ANNEXIN A8 Anxa8 AJ0023900 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 8.3 +/− 1.6 3.8 +/− 0.2 CYCLIN-DEPENDENTCdk4 L01640 0 +/− 0 2.4 +/− 0.2 2.5 +/− 0   3.4 +/− 0.7 5.2 +/− 0.7 3.5+/− 0.1 KINASE 4 INOSITOL POLYPHOS.- Inpp5d U52044 0 +/− 0 1.9 +/− 0.31.9 +/− 0.5 0 +/− 0 3.7 +/− 0.8 4.3 +/− 0.4 5-PHOSPHATASE CYTO. INDUCIB.Cish3 U88328 0 +/− 0 3.6 +/− 0.7 0 +/− 0 0 +/− 0 5.6 +/− 1.5 1.8 +/− 0.2SH2-CONTAINING PROT. 3 FELINE SARCOMA Fes X12616 0 +/− 0 0 +/− 0 0 +/− 00 +/− 0 7 +/− 1 0 +/− 0 ONCOGENE PTP, NON-RECEPT. Ptpn12 X86781 0 +/− 00 +/− 0 0 +/− 0 0 +/− 0 3.2 +/− 1.1 4.9 +/− 0.5 TYPE 12 APLYSIARAS-RELATED Arhb X99963 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 3.5 +/− 0.5   4+/− 0.4 HOMOLOG B Structural Proteins TROPONIN T2, Tnnt2 L47570 0 +/− 00 +/− 0 −1.3 +/− 0.1     4 +/− 2.7 12.4 +/− 5.2  3.4 +/− 1.6 CARDIACNESTIN Nes AF076623 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 6.1 +/− 1.2 0 +/− 0CORONIN, ACTIN Coro1a AF143955 1.8 +/− 0.4 4.1 +/− 0.8 2.9 +/− 0   3.3+/− 0.4 3.3 +/− 0.1 3.7 +/− 1.1 BINDING PROT. 1A MYOSIN HEAVY MyhcaM76601 0 +/− 0 −3.9 +/− 3.9   0 +/− 0 −9.1 +/− 9.4   −8.9 +/− 6.3   −6.6+/− 6  CHAIN, CARDIAC MUSCLE Transcription Factors MYOGENIN Myog D901560 +/− 0 6.9 +/− 5.1 6.6 +/− 2.8 17.2 +/− 13.

15.8 +/− 10.1

0 +/− 0 MYOGENIC DIFFEREN. Myod1 M84918 6.4 +/− 0.9 7.5 +/− 3.1 5.3 +/−3.6 0 +/− 0   8 +/− 3.7 0 +/− 0 1 SFFV PROVIRAL Sfpi1 X17463 0 +/− 0 2.1+/− 0.6 4.2 +/− 0   2.8 +/− 0.3 4.4 +/− 1   8 +/− 1 INTEGRATION 1 ELK3,ETS ONCOGENE Elk3 Z32815 0 +/− 0 2.4 +/− 0.3 2.7 +/− 0.5 0 +/− 0 6.4 +/−0.5 4.6 +/− 0.5 FAMILY INS-1 WINGED HELIX Foxm1 U83112 1.6 +/− 0.5 2.6+/− 0.5 0 +/− 0 2.4 +/− 0.4 3.1 +/− 0.3 4.4 +/− 1.8 INTERFERON REG. Irf1M21065 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 5.4 +/− 2.4 FACT. 1T-CELL ACUTE Tal1 U01530 4.1 +/− 1.7 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0+/− 0 LYMPHOCYTIC LEUKEMIA 1 PEROX. PROLIF. ACTIV. Pparg U09138 0 +/− 00 +/− 0 3.3 +/− 0.4 0 +/− 0 0 +/− 0 4.9 +/− 0.4 RECEPT. GAMMA NFKBINHIB., ALPHA Nfkbia U36277 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.3+/− 0.4 *Genes were assigned to this table after three searches of thePubMed database. The first search looked for papers in which the genename OR an MGI alias were used in the title. The second search lookedfor all papers in which the following terms were used in the title:cartilage OR bone OR chondrogenesis OR osteogenesis OR BMP ORendochondral OR fracture OR osteoblast OR osteoclast. The third searchlooked for the intersection of searches 1 AND 2. If no records warereturned in the third search. then it was determined that there is noexplicit association between the gene and bone or cartilage metabolism.

indicates data missing or illegible when filed

TABLE 7 A correlative analysis of genes having expression profilessimilar to selected marker genes. Similar to Similar to Similar toSimilar to Cyr61 Col2a1 Runx2 Ctsk Genes from Table 5 Scya8 Comp PcolceTcirg1 Cspg2 Crtl1 Col5a1 Itgb3 Cyr61 Col14a1 Lum Ctsk Cdc2a Col9a1Nfatc1 Sdf1 Age Apoe Spp1 Pdgfa Ptprd Bglap-rs1 Mdk Runx2 Bglap1 Col2a1Cdh11 Ckb Fgfr2 Spp1 Car2 Slugh Col5a2 Bmp8a Sfrp3 Bmp1 Tgfbr2 Tnfrsf11bCsf3r TPAR1 col8a1 Tgfbr2 Gja1 Pthr Itgav Mmp13 moucol9a3 Sdc1 Mmp9Col10a1 Bgn Col9a2 Gja1 Vcam1 Genes from Table 6 Myog Fzd1 Pls2 FapSfrp1 Nes Cd9 Sfrp4 Oas1a Anxa8 Irf1 Lifr Ccna2 Epha2 Fyn Lipc Scyb9Serpine2 Ccnd2 Rasa3 Abcb3 Pdgfrb Ptpn12 Arhb Fap Casp6

1-65. (canceled)
 66. A method for assessing the efficacy of a treatmentfor a disease associated with bone or cartilage metabolism in a subjectcomprising the steps of: determining the level or levels of geneexpression of CRLF-1 and/or MMP23 in a first biological sample from thesubject at a time point prior to treatment; determining thecorresponding level or levels of gene expression of CRLF-1 and/or MMP23in a second biological sample from the subject at a time point afterinitiation of treatment; and comparing the level or levels of geneexpression of CRLF-1 and/or MMP23 in the first biological sample withthe corresponding level or levels of gene expression of CRLF-1 and/orMMP23 in the second biological sample, wherein a significant differencebetween the level or levels of gene expression of CRLF-1 and/or MMP23 inthe first and second biological samples indicates that the treatment forthe disease is efficacious.
 67. The method of claim 66, wherein thedisease is associated with bone or cartilage formation.
 68. The methodof claim 66, wherein the disease is associated with bone or cartilageresorption.
 69. The method of claim 68, wherein the treatment comprisesadministration of BMP-2.
 70. A method for monitoring a treatment for adisease associated with bone or cartilage metabolism in a subjectcomprising the steps of: determining the level or levels of geneexpression of CRLF-1 and/or MMP23 in a first biological sample from thesubject at a time point after initiation of treatment; determining thecorresponding level or levels of gene expression of CRLF-1 and/or MMP23in a biological sample or samples from the subject at a later time pointor points; and comparing the level or levels of gene expression ofCRLF-1 and/or MMP23 in the first biological sample with thecorresponding level or levels of gene expression of CRLF-1 and/or MMP23in the later biological sample or samples, wherein the comparisonbetween the level or levels of gene expression of CRLF-1 and/or MMP23 inthe first biological sample and the later biological sample or samplesis an indication of the efficacy of the treatment for the disease. 71.The method of claim 70, wherein the disease is associated with bone orcartilage formation.
 72. The method of claim 70, wherein the disease isassociated with bone or cartilage resorption.
 73. The method of claim72, wherein the treatment comprises administration of BMP-2.
 74. Amethod for identifying a compound which stimulates bone or cartilageformation comprising the steps of: determining the level or levels ofgene expression of CRLF-1 and/or MMP23 in a precursor cell populationcontacted with a test compound; and comparing the level or levels ofgene expression of CRLF-1 and/or MMP23 in the precursor cell populationcontacted with a test compound with the corresponding level or levels ofgene expression of CRLF-1 and/or MMP23 in an uncontacted precursor cellpopulation, wherein a significant difference between the level or levelsof gene expression of CRLF-1 and/or MMP23 in the two precursor cellpopulations indicates that the compound stimulates bone or cartilageformation.
 75. A method for identifying a compound which inhibits boneor cartilage formation comprising the steps of: determining the level orlevels of gene expression of CRLF-1 and/or MMP23 in a precursor cellpopulation contacted with a bone morphogenetic protein and a testcompound; and comparing the level or levels of gene expression of CRLF-1and/or MMP23 in the precursor cell population contacted with the bonemorphogenetic protein and the test compound with the corresponding levelor levels of gene expression of CRLF-1 and/or MMP23 in a precursor cellpopulation contacted only with the bone morphogenetic protein, wherein asignificant difference between the level or levels of gene expression ofCRLF-1 and/or MMP23 in the two precursor cell populations indicates thatthe compound inhibits bone or cartilage formation.
 76. A method fortreating a disease associated with bone or cartilage metabolism in asubject comprising administering to the subject one or more compoundsthat increases the expression and/or activity of CRLF-1 and/or MMP23.77. A method for treating a disease associated with bone or cartilagemetabolism in a subject comprising administering to the subject one ormore compounds that decreases the expression and/or activity of CRLF-1and/or MMP23.